The self-assembly mechanisms of glycyrrhizic acid: Permeation enhancement and transdermal applications.

The self-assembly mechanisms of glycyrrhizic acid: Permeation enhancement and transdermal applications - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Int J Pharm X . 2026 Apr 8;11:100539. doi: 10.1016/j.ijpx.2026.100539 Search in PMC Search in PubMed View in NLM Catalog Add to search The self-assembly mechanisms of glycyrrhizic acid: Permeation enhancement and transdermal applications Lin Zhou Lin Zhou a Dermatology Hospital, Southern Medical University, Guangzhou 510091, China b School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China Find articles by Lin Zhou a, b, 1 , Youran Deng Youran Deng b School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China Find articles by Youran Deng b, 1 , Mingjie Ou Mingjie Ou b School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China Find articles by Mingjie Ou b , Zhuxian Wang Zhuxian Wang a Dermatology Hospital, Southern Medical University, Guangzhou 510091, China Find articles by Zhuxian Wang a, ⁎ Author information Article notes Copyright and License information a Dermatology Hospital, Southern Medical University, Guangzhou 510091, China b School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China ⁎ Corresponding author. [email protected] 1 These authors contributed equally to this work. Received 2026 Feb 22; Revised 2026 Mar 24; Accepted 2026 Apr 7; Collection date 2026 Jun. © 2026 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). PMC Copyright notice PMCID: PMC13092070  PMID: 42011262 Abstract Glycyrrhizic acid (GA) is an amphiphilic triterpenoid saponin compound derived from licorice. This review first summarizes the behaviors and evolution mechanisms of GA forming different nanostructures (dimers, micelles, nanoparticles, nanofibers, and hydrogels) under varying conditions (concentration, temperature, pH, ionic strength) and intermolecular forces. Subsequently, it introduces the transdermal permeation enhancement and bioavailability improvement of hydrophobic drugs when encapsulated by GA. GA significantly enhances drug solubility and stability, promotes drug penetration, and improves targeted delivery efficiency, thereby increasing transdermal bioavailability. Finally, the functions of GA in transdermal drug delivery and its penetration enhancement mechanism are elucidated. It primarily enhances permeation by altering the arrangement of stratum corneum (SC) lipids and keratin, ultimately weakening the skin barrier. This review reveals principles dominating the self-assembly and permeation enhancement of GA, providing a paradigm for the self-assembly of other natural products and offering references for further applications of GA in transdermal drug delivery. Keywords: Glycyrrhizic acid, Self-assembly, Transdermal drug delivery, Permeation enhancement, Bioavailability Graphical abstract Open in a new tab 1. Introduction Licorice, primarily derived from the dried roots and rhizomes of Glycyrrhiza glabra L., G . uralensis Fisch. , and G. inflata Bat. , is a traditional Chinese medicinal herb with a long history of use. GA, also known as glycyrrhizin, is the major active component of licorice ( Jung et al., 2025 ). It is an amphiphilic saponin composed of a triterpenoid aglycone (18β-glycyrrhetinic acid) and disaccharide glucuronic acid moieties ( Ni et al., 2022 ; Rasool and Dar, 2025 ; Song et al., 2022 ). GA exhibits multiple pharmacological bioactivities, including anti-inflammatory( Zheng et al., 2021 ), antiviral( Sun et al., 2021 ), antioxidant, anti-allergic, immunomodulatory, and antitumor effects( Guo et al., 2025b ; Su et al., 2025 ; Zeng et al., 2024 ; Zuo et al., 2023 ). It exhibits multi-pathway and multi-target synergistic mechanisms in skin protection. First, GA directly mitigates ultraviolet B (UVB)-induced photoaging in human fibroblasts by significantly reducing intracellular reactive oxygen species (ROS) levels and inhibiting the activation of NF-κB, thereby blocking the activation of matrix metalloproteinase-1 (MMP-1) ( Afnan et al., 2012 ; Aluc et al., 2022 ). Moreover, GA exhibits significant chemopreventive activity against TPA-induced skin damage. It alleviates oxidative stress at its source by markedly reducing lipid peroxidation, restoring endogenous antioxidant (e.g., glutathione) activity, and suppressing pro-proliferative signals like ornithine decarboxylase (ODC) activity and excessive DNA synthesis, thereby maintaining skin cell homeostasis ( Jain et al., 2022 ; Rahman and Sultana, 2008 ). As a result, GA is broadly used to treat various skin disorders, particularly dermatitis, eczema, pruritus, cysts, psoriasis, and melasma. GA is a typical amphiphilic triterpene saponin in nature. It spontaneously aggregates in water, with hydrophobic regions facing inward and hydrophilic regions outward ( Trindade et al., 2025 ). This distinct amphiphilic structure enables it to function as an effective natural excipient and active carrier in drug delivery systems. Owing to its amphiphilicity, GA can self-assemble into various nanostructures—including dimers, micelles, nanoparticles, nanofibers, and hydrogels under different conditions. Their assembly behavior is highly dependent on pH, temperature, ionic strength, and concentration ( Xiao et al., 2024a ). However, no literature has comprehensively summarized the self-assembly behaviors, driving forces, and mechanisms of GA. Its self-assembly is dynamic and multi-step, and the evolutionary pathways from molecules to nanoaggregates have been scarcely reported. In traditional Chinese pharmacology, GA is known for its "harmonizing" property, which enhances the solubility and stability of the co-administered drugs in transdermal drug delivery. Consequently, it promotes drug permeation and enables targeted delivery and sustained release, which ultimately improves efficacy while reducing adverse effects. GA is capable of forming micelles, nanoparticles, or hydrogels with hydrophobic drugs during skin permeation ( Albalawi and Khateeb, 2025 ; Lu et al., 2025 ; Xiao et al., 2024b ; Zhao et al., 2024a ). However, their co-assembly behaviors, permeation enhancement properties, and mechanisms are poorly understood. In recent years, several reviews have systematically summarized the medicinal value of GA from various perspectives. Stecanella et al. detailed the application of GA and its hydrolyzed metabolite, 18β-glycyrrhetinic acid, as liver-targeting ligands in nano-delivery systems for active hepatocellular carcinoma therapy ( Stecanella et al., 2021 ). Diomede et al. focused on its antiviral activity, particularly the potential mechanisms against SARS-CoV-2 involving interactions with ACE2, the spike protein, and 3CLpro ( Diomede et al., 2021 ). Furthermore, Sharifi-Rad et al. provided a comprehensive phytochemical review of Glycyrrhiza species, highlighting their broad pharmacological activities, including antioxidant, anti-inflammatory, antibacterial, and anticancer effects ( Sharifi-Rad et al., 2021 ). However, no reviews have addressed the intrinsic self-assembly behavior of GA or its consequent applications in transdermal drug delivery to the best of our knowledge. Therefore, this review first summarizes the behaviors and mechanisms of GA self-assembly into dimers, micelles, nanoparticles, nanofibers, and hydrogels under various conditions (concentration, temperature, pH, ionic strength) and intermolecular interactions. Subsequently, it systematically reviews the behaviors, bioavailability enhancement, and applications of GA as a pure or composite delivery carrier in drug delivery, including micelles, fibers, and hydrogels. Next, it summarizes the role of GA in transdermal delivery and its permeation-enhancing mechanisms ( Fig. 1 ). This review reveals fundamental principles of amphiphilic GA self-assembly, deepens the understanding of supramolecular chemistry and noncovalent interactions, and provides a paradigm for the self-assembly studies of other natural products. Fig. 1. Open in a new tab Schematic illustration of GA self-assembly, GA transdermal drug delivery systems, and permeation enhancement in transdermal application. 2. GA self-assembly behaviors and mechanisms 2.1. Mechanisms and morphological characteristics of GA self-assembly into dimers The self-assembly behavior of GA is primarily driven by molecular amphiphilicity and synergistically regulated by pH, temperature, ionic strength, and various intermolecular forces ( Wu et al., 2013 ). Under different external conditions and driving forces, GA can self-assemble into various forms of nanostructures. Without drug loading, GA molecules first promote the proximity of hydrophobic aglycones through hydrophobic interactions, forming dimers as the core structural unit. The dimer can be further stabilized by various conditions and intermolecular forces, such as hydrogen bonding and π-π stacking ( Table 1 ). Table 1. The formation conditions, structural features, and characterization methods of dimer configurations. Dimer Configuration Formation Conditions Structural Features Characterization Methods Key Differences References L-shaped lateral stacking pH = 4 - 7 25 °C Dimer thickness ∼2.5 - 2.8 nm, forms helical fibers with a pitch of 9 nm AFM, WAXS, SAXS (Slope -1.64) First proposal of GA dimers as lateral stacks forming helical fibers ( Saha et al., 2015 ) An alternative drug More compact building block pH = 4 - 7 Heated to 80 °C, then cooled Dimer is more compact, diameter ∼2.3 nm, glycosyl groups exposed, pitch 9 nm. SAXS/SANS, WAXS (0.61 nm spacing) The revised Saha model proposed a more compact dimer structure ( Denk et al., 2023 ) Host-guest complex at low concentration Low concentration (<1 mM) CAC = 2.38 mmol/L Simulation condition: 298 K Dimeric cyclic structure capable of encapsulating hydrophobic drugs MD, DLS, ITC Emphasizes the dimer's role as a drug carrier at low concentrations ( Qi et al., 2023 ) Tail-to-Tail Hydrophobic Core-Shell Configuration pH < pKa₃ (≈5.17) CAC = 0.22 ± 0.04 mM Low ionic strength (Milli-Q water) 25 °C Dimer diameter ∼3.6 nm (SANS) → 4.2 nm (SAXS), hydrophobic core, hydrophilic shell SANS/SAXS, cryo-TEM, MD Criticized the Saha and Denk models, proposed a tail-to-tail configuration ( Trindade et al., 2025 ) Tail-to-Tail Hydrophobic Core-Shell Configuration pH = 4 - 6.5 CMC ≈ 0.22 - 0.38 mM (pH=5.1-5.5) Low ionic strength 25 °C core-shell structure core diameter 1.5 nm shell extends to 2.1 nm SAXS/SANS, MD simulation, CPP theoretical analysis Proposed tail-to-tail configuration from a surfactant perspective, emphasizing non-classical micellization ( Cai et al., 2025 ) Open in a new tab 2.1.1. Morphological characteristics in different isomer configurations of dimers Previous studies held differing views on the configuration of GA dimers. Saha et al. ( Saha et al., 2015 )first proposed that GA molecules adopt a “L-shaped lateral stacking” arrangement ( Fig. 2 a) to form dimers, which then further stack helically to form nanofibers, as evidenced by atomic force microscopy (AFM) and wide-angle X-ray scattering (WAXS). However, this configuration faced challenges in explaining the nanofiber dimensions observed in subsequent scattering experiments. To address this limitation, Denk et al. ( Denk et al., 2023 )put forward a more compact folding configuration ( Fig. 2 b) through meticulous fitting of the data of small-angle X-ray/neutron scattering (SAXS/SANS). This model posits that the glycosidic backbone of GA molecules in the dimer adopts a more efficient packing arrangement, with greater exposure of the sugar moieties to the aqueous phase. Fig. 2. Open in a new tab The self-assembly mechanisms of GA Dimers. (a) Initial L-shaped lateral stacking configuration proposed by Saha et al. (b) Refined compact dimer configuration from Denk et al. (c) Tail-to-tail GA dimer configuration proposed herein based on molecular dimensions from Denk et al. (d) Schematic of the pH-dependent self-assembly pathways and resulting GA structures. (a,b) Adapted from "Glycyrrhizic acid aggregates seen from a synthetic surfactant perspective" by Fischer and Lutz-Bueno, 2024 , Phys. Chem. Chem. Phys., 26, 2806, under CC BY 3.0 License; (c) Reproduced with permission from S. G. Trindade, F. B. Okasaki, A. P. Williams, E. Sabadini, and V. Lutz-Bueno, "The self-assembly of glycyrrhizic acid into nanofibrils," J. Colloid Interface Sci., 2025, 699, Part 2, 138280, DOI: 10.1016/j.jcis.2025.138280. Copyright 2025, Elsevier; (d) Adapted with permission from J. Cai, Y. Liu, L. Ma, S. Liu, Z. Wan, and X. Yang, "pH-responsive self-assembly of natural saponin glycyrrhizic acid," J. Colloid Interface Sci., 2025, 700, Part 2, 138511, DOI: 10.1016/j.jcis.2025.138511. Copyright 2025, Elsevier. Recently, multiple studies have critically examined and advanced the aforementioned configuration. Based on comparative scattering experiments and molecular dynamics (MD) simulations, Trindade and Lutz-Bueno ( Trindade et al., 2025 ), and Fischer and Lutz-Bueno ( Cai et al., 2025 ) jointly proposed a novel “tail-to-tail” hydrophobic interaction configuration ( Fig. 2 c). This configuration suggests that the hydrophobic glycosidic tails of two GA molecules bind to each other through strong hydrophobic interactions, forming the inner core of the dimer, while the hydrophilic glucuronic acid heads extend outward to form a hydrated shell. The diameter of the inner core and the overall diameter of the outer shell were measured using SANS and SAXS, which differ from the core-shell structure. This difference provides crucial evidence for the “tail-to-tail” core-shell structure ( Fig. 2 d) ( Cai et al., 2025 ; Trindade et al., 2025 ). Moreover, the configuration successfully reconciles seemingly contradictory scattering size data from previous studies. Additionally, Qi et al. ( Qi et al., 2023 ) focused on another functional form of dimers at low concentrations. They proposed that GA forms “host-guest complexes” with dimers as the basic structural units near the critical aggregation concentration. Their ring-shaped structure provides a hydrophobic cavity capable of encapsulating other hydrophobic drug molecules, indicating that GA dimers are not only structural units but also possess direct functional application potential. Collectively, the typical diameter of GA dimer ranges between 2.3–4.2 nm, with specific values depending on the measurement method and environmental conditions. The prevailing view supports a “tail-to-tail” hydrophobic core-shell configuration, where the hydrophobic aglycone core measures approximately 1.5 nm in diameter, and the hydrophilic sugar chain shell extends to 2.1–2.5 nm, jointly forming a pH-responsive asymmetric structure. This configuration not only explains most scattering and microscopic observation results but also provides the structural basis for its function as a drug carrier. The currently accepted mainstream configuration of GA dimers is the “tail-to-tail” hydrophobic core-shell structure, which reasonably explains the size data obtained from scattering experiments and provides a structural basis for its function as a drug carrier. In contrast, the early-proposed “L-shaped lateral stacking” configuration, although it first revealed the existence of dimers, predicted fibril dimensions inconsistent with subsequent scattering results. The “more compact building block” configuration, despite improvements in fitting accuracy, underestimated the contribution of hydrophobic interactions and failed to fully elucidate the dynamic assembly behavior of dimers in solution. 2.1.2. Formation conditions for GA self-assembly into dimers The formation and stability of GA dimers are regulated by multiple external factors, including pH, temperature, ionic strength, and GA concentration. From a thermodynamic perspective, the formation of dimers is an entropy-driven hydrophobic assembly process. As hydrophobic monomers undergo desolvation, they displace ordered water molecules, resulting in an increase in the system's entropy (ΔG < 0). (1) pH value: This is the most critical factor regulating GA dimer formation. The pKa values of the three carboxyl groups in GA are 3.98, 4.62, and 5.17, respectively. Within the pH range of 4.5–6.0, increased protonation of the carboxyl groups enhances the overall hydrophobicity of the molecule, favoring dimer formation and stability. When pH > 7, the carboxyl group becomes fully ionized, generating strong electrostatic repulsion between molecules, leading to dimer dissociation or difficulty in formation ( Baccile et al., 2021b ). Nuclear Magnetic Resonance Spectroscopy (NMR) studies further confirm that GA molecules tend to aggregate into micellar structures in water/methanol mixtures with pH ≤ 5, with dimers serving as their fundamental building blocks ( Petrova et al., 2017 ). (2) Temperature: Temperature predominantly affects dimer stability. Within the range of 25–40°C, the dimer structure remains stable, with hydrogen bond networks and hydrophobic stacking maintained ( Denk et al., 2023 ). When temperatures exceed 55°C, thermal energy disrupts the hydrogen bond networks sustaining the dimer structure and enhances molecular thermal motion, leading to dimer dissociation and transformation into globular structures ( Denk et al., 2023 ; Fischer and Lutz-Bueno, 2024 ). This thermoreversible transition indicates that the stability of the dimer is governed by the enthalpy-entropy balance. (3) Ionic Strength: Ion concentrations affect dimer formation and stability by shielding charges. In low ionic strength conditions (<50 mM), unshielded carboxylate negative charges generate electrostatic repulsion, maintaining a dynamic equilibrium between monomers and dimers. Conversely, high ionic strength shields charge repulsion, promoting dimer formation. (4) GA concentration: The critical aggregation concentration (CAC) of GA is a key parameter determining its dimer formation. Experiments indicate that the CAC of GA is 0.22 ± 0.04 mM in aqueous solution (25°C) ( Cai et al., 2025 ; Trindade et al., 2025 ). Below this concentration (<1 mM), GA molecules spontaneously form stable dimer units via hydrophobic aglycone interactions, serving as “host-guest complex” carriers for hydrophobic drugs without large-scale aggregation occurring ( Qi et al., 2023 ). Notably, the CAC is significantly lower than the critical micelle concentration (CMC) of conventional micelles, indicating that dimer formation is an intermolecular binding process independent of micellization ( Cai et al., 2025 ). CAC exhibits pronounced pH dependence: at pH=4, where carboxylate protonation enhances hydrophobic interactions, CAC drops to 0.05 mM; whereas in neutral aqueous solutions (pH≈7), CAC rises to 0.26 mM ( Cai et al., 2025 ; Trindade et al., 2025 ). 2.1.3. Driving forces for ga self-assembly into dimers The formation of GA dimers results from the synergistic interactions of multiple noncovalent bonds. Different external conditions ultimately stabilize distinct dimer configurations by modulating the equilibrium of these forces. In the “tail-to-tail” hydrophobic core-shell configuration, hydrophobic interactions are the primary driving force. The hydrophobic glycosidic tails of the two GA molecules bind directly to one another via hydrophobic effects, forming a dense, fully dehydrated nonpolar core. This process is a spontaneous, entropy-driven process in which the desolvation of hydrophobic groups releases ordered water molecules, leading to an increase in the system’s entropy. Hydrogen bonding exhibits a dual role. On the one hand, the hydrogen bond network between the uronic acid heads stabilizes the hydrophilic shell, enhancing the structure’s solubility; on the other hand, under specific pH conditions (e.g., pH < 5), carboxyl protonation promotes the formation of intermolecular hydrogen bonds, thereby enhancing the stability of the dimer. Electrostatic interactions act as a “switch” in this configuration. Under weakly acidic conditions (pH < pKa₃ ≈ 5.17), partial protonation of the carboxyl group reduces the electrostatic repulsion between the glucuronic acid heads, allowing hydrophobic interactions to dominate and form a compact “tail-to-tail” structure. When the pH rises to neutral or basic conditions, the carboxyl group becomes fully ionized, and strong electrostatic repulsion causes the dimer to dissociate. In contrast, in the earlier “lateral L-stacking” configuration, hydrogen bonding and π-π stacking were considered the key forces stabilizing the dimer ( Fischer and Lutz-Bueno, 2024 ). However, this configuration struggles to explain the size data observed in subsequent scattering experiments, suggesting that its contribution to hydrophobic interactions was underestimated. The “compact folding” configuration, on the other hand, places greater emphasis on the dominant role of hydrophobic interactions, supplemented by van der Waals forces to stabilize the dense packing ( Fischer and Lutz-Bueno, 2024 ). From a kinetic perspective, dimer formation is a rapid, reversible nucleation process. At concentrations approaching the CAC, hydrophobic interactions drive GA molecules to collide and form dimers; this process is diffusion-controlled, occurring on a timescale of nanoseconds to microseconds. Once formed, dimers serve as structural building blocks for subsequent nanofiber growth. 2.2. Mechanism and characteristics of GA self-assembly into micelles Similar to the formation of dimers, the micellization process is also a thermodynamically driven spontaneous process, driven by a decrease in the system’s free energy (ΔG < 0) resulting from hydrophobic interactions. When the GA concentration exceeds its CMC, the system drives the assembly of monomer molecules into micelles to reach the state of minimum free energy. Unlike dimers, micelles are equilibrium structures whose size and shape are determined under given thermodynamic conditions (pH, temperature, and ionic strength). ( Table 2 ) Table 2. The morphology, preparation method, formation conditions, driving forces and characterization methods of GA micelles Micelle Morphology Morphological Parameters Preparation Method Formation Conditions Driving Forces Characterization Methods Main Conclusions References Rod-like micelles Radius ≈1.5 nm, Length ≈21 nm (pH=5) Radius ≈1.3 nm, Length ≈18 nm (pH=6) / pH = 5-6, Temperature 25 °C, CMC = 2.9 mM (pH=5), CMC = 5.3 mM (pH=6) Hydrophobic interactions Surface tension, fluorescent probe (pyrene), light scattering, SAXS, TEM GA forms rod-like micelles under weakly acidic conditions, similar to bile salt behavior; micelles dissociate at pH > 7. ( Matsuoka et al., 2016 ) Ellipsoidal micelles (Slightly anisotropic) Core radius R₁ = 14 Å; Shell radius R₂ = 16 Å; Ellipticity ee = 17 ± 2; Aggregation number ≈150; Length ≈270 Å, increases with electrolyte addition. / pH = 4-5 CAC ≈ 0.1 mM, Electrolytes (e.g., NaCl) promote micelle growth Hydrophobic interactions, and hydrogen bonds stabilize the hydrophilic shell Neutron Reflectivity (NR), Small-Angle Neutron Scattering (SANS) GA forms core-shell micelles; saturated adsorption amount 1.85×10 -10 mol/cm 2 ; gelation has no significant effect on adsorption. ( Tucker et al., 2021a ) Micelle microspheres Diameter ∼10 nm Sonication Low concentration (<10 mg/mL) GA amphiphilic structure, sonication energy driven TEM, DLS, ζ-potential GA micelles can serve as confined microdomains for crystallization templates and drug loading. ( Liu et al., 2025b ) Spherical micelles Average particle size ∼75 nm; Micelle size distribution: 86.33 ± 2.9 nm (GA:Cur=5:1) Thin-film hydration method CMC = 0.021 wt% (approx. 0.255 mM); Temperature: 37 °C Hydrophobic interactions, Hydrogen bonding DLS, Fluorescence spectroscopy, SEM, TEM, UV/Vis GA micelles further form hydrogels; high stability (Zeta potential -42.2 mV) and good encapsulation efficiency (EE% 80.17%). ( Zheng et al., 2023b ) Rod-like micelles Diameter 1.5-2.0 nm / pH = 5-6; Temperature: 298.2 K; CMC = 1.5 mM (pH=5), CMC = 3.7 mM (pH=6); Ion concentration: Phosphate buffer (0.05 M) Hydrophobic interactions Surface tension, Light scattering, SAXS, TEM, cryo-TEM GA forms micelles only under weakly acidic conditions, no micelle formation at pH ≥ 7. Micelle morphology is rod-like. ( Matsuoka et al., 2021 ) Open in a new tab 2.2.1. Morphological characteristics and parameters of micelles The morphology of GA micelles exhibits significant pH dependence. Under weakly acidic conditions (pH=4–6), GA tends to form rod-like or fibrous micelles ( Tucker et al., 2021b ). Matsuoka et al. ( Matsuoka et al., 2021 ; Matsuoka et al., 2016 ) observed that GA forms rod-like micelles with a radius of approximately 1.5 nm and a length of about 21 nm at pH=5, and slightly reduced dimensions at pH=6 via SAXS and transmission electron microscopy (TEM). Tucker group ( Tucker et al., 2021a ) further revealed that GA forms ellipsoidal core-shell micelles at pH=4–5, featuring a core radius of approximately 14 Å with an outer shell extending to 16 Å, an aggregation number of about 150, and a total length of approximately 270 Å verified by SANS. These studies collectively support the conclusion that rod-shaped and ellipsoidal micelles are the primary assembly forms of GA under weakly acidic conditions. Furthermore, Liu et al. ( Liu et al., 2025b ) demonstrated that ultrasonication can induce self-assembly of GA in low-concentration solutions (<10 mg/mL) to form micelles with diameters around 10 nm. These micelles serve as nanoreactors or confined microdomains. Overall, it is currently widely accepted that, in weakly acidic aqueous solutions without external agitation (such as ultrasound), GA primarily forms rod-shaped or ellipsoidal micelles at the nanoscale, which exhibit a core-shell structure ( Zheng et al., 2023b ). Under this condition, the rigid triterpenoid skeleton restricts the curvature of the core and promotes anisotropic growth. In contrast, spherical micelles appear only transiently under external energy input such as ultrasonication, representing a kinetically trapped state rather than a thermodynamically equilibrated structure. Fibrous aggregates, on the other hand, typically form when the concentration approaches the critical gelation concentration, exceeding the typical micelle regime and representing an intermediate state toward hydrogel formation. 2.2.2. Formation conditions for GA self-assembly into micelles The formation and stability of GA micelles are jointly regulated by pH, temperature, ion concentration, and concentration of GA. From a thermodynamic perspective, micellization is an entropy-driven process: as hydrophobic monomers undergo desolvation, they release ordered water molecules, increasing the system’s entropy. This overcomes the enthalpy loss caused by electrostatic repulsion, resulting in a decrease in total free energy. (1) pH: pH is the most critical factor regulating GA micelle formation and morphology. GA typically forms micelles within a weakly acidic range (pH 5-6). This occurs because the ionization states of the three carboxyl groups in the GA molecule influence its hydrophilic-hydrophobic balance ( Selyutina and Polyakov, 2019a ; Tucker et al., 2021a ). At pH ≤ 5, the carboxyl groups become partially protonated, increasing the overall hydrophobicity of the molecule and weakening electrostatic repulsion. This promotes micellization driven by hydrophobic interactions; at this point, ΔG < 0, and micelles form spontaneously. When pH rises to 6, partial ionization increases hydrophilicity, diminishing micelle formation capacity, and ΔG increases. At pH ≥ 7, the carboxyl groups are fully dissociated, and strong electrostatic repulsion makes micellization thermodynamically unfavorable (ΔG ≥ 0). Thus, GA exists in its monomeric form and cannot form micelles. (2) Temperature: Temperature influences the self-assembly kinetics and thermodynamic equilibrium of GA micelles. Micelle formation occurs rapidly at 25°C, reflecting favorable kinetics. High temperatures (e.g., 60°C) can promote molecular motion, but they may also disrupt the hydrogen bond network that maintains micelle stability, leading to micelle dissociation. Therefore, there exists an optimal temperature range within which the contributions of enthalpy and entropy are in equilibrium. (3) Ionic Strength: Ionic strength influences micelle stability by shielding charges. High ionic strength (e.g., >100 mM NaCl) can mask the electrostatic repulsion between the negative charges on carboxyl groups, reducing the free energy required for micellization and thereby promoting micelle formation and aggregation. However, excessively high ionic strength may lead to excessive micelle aggregation or even precipitation (!!! INVALID CITATION !!! ( Matsuoka et al., 2021 ; Zhang et al., 2021 )). (4) Concentration: Micelle formation requires GA concentrations that are above the CMC ( Barthel et al., 2023 ). The CMC is approximately 2.5 mM (0.03 wt%) at pH=5. When the concentration exceeds the CMC, the minimization of the system’s free energy drives monomer molecules to assemble into micelles, and the number of micelles increases with rising concentration. As the concentration further increases to the critical gelation concentration (e.g., 2 wt%), the micelles may entangle or cross-link, forming a thermoreversible hydrogel. This marks the transition from zero-dimensional micelles to a three-dimensional network ( Zhang et al., 2021 ). 2.2.3. Driving Forces for GA Self-Assembly into Micelles The driving force behind the self-assembly of GA into micelles is similar to that of conventional surfactants, but its rigid triterpenoid structure determines the unique morphology of the micelles. (1) Hydrophobic Interaction: This constitutes the primary driving force for GA micelle formation, and it is also the main source of the decrease in the system’s free energy. The triterpenoid aglycone moiety of GA exhibits strong hydrophobicity, tending to aggregate in aqueous environments to minimize water contact, thereby forming micelle cores ( Tucker et al., 2024 ). Unlike the “tail-to-tail” structure driven by hydrophobic interactions in dimers, the hydrophobic groups of a large number of molecules aggregate to form a liquid hydrophobic core in micelles. The rigid triterpenoid structure of GA molecules restricts the curvature of the core, causing it to form rod-shaped rather than spherical micelles ( Matsuoka et al., 2016 ; Tucker et al., 2024 ). (2) Hydrogen Bonding: Hydrophilic glucuronic acid groups form hydrogen bonding networks with each other and water molecules. Its primary function is to stabilize the hydrophilic shell of the micelle and prevent excessive penetration of water molecules ( Tucker et al., 2024 ). In contrast to hydrogen bonds in dimers, which act as “molecular locks” to stabilize specific conformations, hydrogen bonds in micelles primarily function as a collective stabilizing force, imparting a certain degree of rigidity and hydration capacity to the shell. 2.3. Mechanism and properties of GA self-assembly into nanoparticles Unlike dimers and micelles, the formation of nanoparticles typically involves more complex nucleation-growth processes, and their morphology and stability are significantly influenced by the preparation method and environmental factors ( Table 3 ). Table 3. The morphology, preparation method, formation conditions, driving forces, and characterization methods of GA nanoparticles Nanoparticle Morphology Morphological Parameters Preparation Method Driving Forces References Spherical Nanoparticles (GANPs) Average particle size ≈70.65 nm; Spherical, uniform distribution; ζ-potential ≈ -32.7 mV Hydrothermal synthesis: 185 °C, pH = 9.0 ± 0.2 Hydrogen bonding, Hydrophobic interactions, π-π stacking ( Zhao et al., 2021 ) Spherical Nanoparticles Diameter ∼30 nm Aqueous phase, acidic conditions, sonication Hydrogen bonding, Electrostatic interactions, Hydrophobic interactions ( Rao et al., 2023 ) Spherical Nanoparticles (GL-SSD) Average diameter 207 nm (GL-SSD), Pure GL ∼30 nm Aqueous phase, acidic conditions, Sonication + Dialysis Electrostatic attraction, Hydrogen bonding, Van der Waals forces ( Wei et al., 2024 ) Self-assembled Nanoparticles (hydrophilic domain outside, hydrophobic domain inside) Particle size not directly given, simulation system size 6×6×6 nm 3 Aqueous environment, CAC = 2.38 mmol/L, Temperature 298 K (simulation) Hydrogen bonding, Hydrophobic interactions ( Qi et al., 2023 ) Core-Shell Structure (GAN-OMV) Spherical, uniform. GANs: 104 ± 1.66 nm; GAN-OMV: 130.43 ± 9.73 nm pH = 7.4 (PBS), Mechanical extrusion method, GA concentration 100 μg/mL Hydrophobic interactions, Hydrogen bonding, Electrostatic interactions ( Huang et al., 2022 ) Open in a new tab 2.3.1. Morphological characteristics and parameters of nanoparticles GA self-assembled nanoparticles predominantly exhibit spherical morphology with a narrow particle size distribution and negative surface charge. However, there are discrepancies in the particle sizes reported in different studies, which are primarily attributed to differences in preparation methods. Zhao et al. ( Zhao et al., 2021 ) synthesized pure GA nanoparticles (GANPs) in alkaline hydrothermal conditions (pH 9.0, 185°C). TEM images reveal uniform spherical morphology. Dynamic light scattering (DLS) measurements indicate an average hydrodynamic diameter of 70.65 nm and a zeta potential of -32.7 mV, confirming their negatively charged surfaces and excellent colloidal stability. Additionally, these nanoparticles exhibited characteristic UV absorption at 267 nm and blue fluorescence emission (λex = 356 nm, λem = 438 nm), indicating quantum dot-like optical properties. This fluorescent behavior suggests that hydrothermal treatment may have induced chemical changes in the GA molecules or highly ordered stacking, rather than merely physical self-assembly. In contrast, Rao et al. ( Rao et al., 2023 ) observed that pure GA forms spherical nanoparticles with a diameter of approximately 30 nm and a zeta potential of -31 mV. Wei et al. ( Wei et al., 2024 ) found that the pure GA exhibited a spherical structure when co-assembled with Spinosad, further validating GA's inherent capability to form nanoparticles. From a theoretical modeling perspective, molecular dynamics simulations ( Qi et al., 2023 ) demonstrated that 10 GA molecules in aqueous solution (within a 6×6×6 nm 3 box) could self-assemble into nanoparticles over 50 ns. The structure exhibits a core-shell arrangement, with the hydrophilic regions on the outside and the hydrophobic regions on the inside. Furthermore, Huang et al. ( Huang et al., 2022 ) fused GANs with bacterial outer membrane vesicles (OMVs) to construct GAN-OMV complexes with a core-shell structure. TEM images revealed spherical GANs possessed an average size of 104 nm, while the fused GAN-OMV increased to 130 nm with a zeta potential of -30.4 mV, indicating good dispersity and stability. This structure was prepared via mechanical extrusion in phosphate buffer at pH 7.4. The hydrophobic aglycone core aggregates through hydrophobic interactions, while the hydrophilic sugar chain shell stabilizes the overall structure via hydrogen bonds and electrostatic forces. Collectively, spherical nanoparticles represent the primary assembly morphology of GA under high concentrations or specific energy-input conditions. However, the particle sizes reported vary significantly depending on the preparation method. Mild conditions tend to yield smaller particles of approximately 30 nm, whereas hydrothermal treatment promotes the formation of larger particles (approximately 70 nm), indicating that particle size is governed by both kinetic and thermodynamic factors. Additionally, at concentrations near the critical aggregation concentration, GA preferentially forms dimers rather than stable nanoparticles, suggesting that nanoparticle formation requires relatively high molecular concentrations or external energy input. 2.3.2. Formation conditions for GA self-assembly into nanoparticles The self-assembly process of GA into nanoparticles is highly dependent on temperature, pH, ion concentration, and solvent system. (1) Temperature: Temperature influences GA self-assembly kinetics and thermodynamic equilibrium. Under elevated temperature conditions (e.g., 185°C hydrothermal method), increased molecular thermal motion overcomes the energy barrier for nucleation, promoting hydrophobic stacking and spherical particle formation ( Wei et al., 2024 ). At 25°C, GA molecules self-assemble under mild conditions, though the process may proceed more slowly. (2) pH: The pH value influences the self-assembly process by regulating the ionization state of GA molecules. Under alkaline conditions (pH 9.0), the carboxyl groups in GA molecules undergo complete ionization, enhancing intermolecular electrostatic repulsion and promoting the formation of uniform nanoparticles ( Wei et al., 2024 ). In weakly alkaline environments (pH 7.4–8.0), GA molecules can also achieve self-assembly through delicate charge balancing, as demonstrated in preparation processes such as mechanical extrusion ( Huang et al., 2022 ). Notably, reduced carboxyl group ionization increases molecular hydrophobicity at lower pH conditions, potentially leading to particle aggregation. (3) Preparation Methods: The choice of preparation method affects the final morphology of nanoparticles and particle size distribution. The hydrothermal method with high temperature and pressure provides additional energy, promotes nucleation, and accelerates growth, typically resulting in larger nanoparticles with fluorescent properties. In contrast, the film hydration method, ultrasonic method, or mechanical extrusion method is carried out under milder conditions, yielding smaller particles that are closer to thermodynamic equilibrium ( Huang et al., 2022 ; Wei et al., 2024 ). 2.3.3. Driving forces for GA self-assembly into nanoparticles (1) Hydrogen Bonding: Hydrogen bonding plays a pivotal role in stabilizing the hydrophilic shell of nanoparticles. Within pure GA systems, intermolecular carboxyl and hydroxyl groups form extensive hydrogen bond networks. These bonds act as “molecular locks,” stabilizing nanoparticle structures ( Wei et al., 2024 ). Spectroscopic studies confirm that hydrogen bonding not only contributes to the formation of hydrophilic shells but also enhances particle solubility and stability ( Qi et al., 2023 ; Rao et al., 2023 ). Contrary to the “collective stabilizing effect” of the outer shell in micelles, the hydrogen-bond network in nanoparticles is denser and may involve multipoint intermolecular connections. (2) Electrostatic Interaction and Van der Waals Forces: Electrostatic interaction plays a crucial role in maintaining nanoparticle stability. The ionization of carboxyl groups in GA molecules endows the nanoparticle surface with a negative charge, and the resulting electrostatic repulsion effectively prevents excessive particle aggregation, which confers good colloidal stability on the system ( Huang et al., 2022 ; Rao et al., 2023 ). From a kinetic perspective, this electrostatic repulsion increases the energy barrier for interparticle collisions, thereby slowing the aggregation rate. Van der Waals forces, on the other hand, provide additional attractive forces in close molecular packing, contributing significantly, especially in compact structures ( Chen et al., 2022 ; Wei et al., 2024 ). 2.4. Mechanism and properties of GA self-assembly into nanofibers and hydrogels Due to their amphiphilic structure, GA molecules can self-assemble into one-dimensional nanofibers in aqueous solutions. These fibers further entangle to form three-dimensional networks, thereby yielding supramolecular hydrogels. Consequently, nanofibers serve as the structural foundation of hydrogels, and the formation of both is a continuous, unified, and hierarchical self-assembly process ( Li et al., 2022 ). This section will provide an integrated discussion of the evolution mechanism from nanofibers to hydrogels, as well as the synergistic interaction between structural features and driving forces ( Table 4 ). Table 4. The morphology, preparation method, formation conditions, driving forces, and characterization methods of GA nanofibers Nanofiber Morphology Morphological Parameters Formation Conditions Driving Forces Key Conclusions References Semiflexible nanofibrils Diameter ∼2.5 nm (based on bulk solution AFM) pH = 2 - 4: Forms fiber aggregates or nanofibers; pH > 5: Micelles or monomers; T > 55 °C: fiber dissociation Hydrophobic interactions, Hydrogen bonding pH and temperature regulate GA assembly morphology at the interface; fibrous structures enhance interfacial elasticity. ( Cai et al., 2024 ) pH-responsive nanofibrils pH=4: Diameter 3.8±0.4nm, Length 71.9±2.3nm; pH=4.3: Diameter 4.0±0.3nm, Length 65.7±3.2nm pH = 4 - 4.3 forms nanofibers, pH < 4 forms fiber bundles, pH > 5 dissociates into spherical aggregates, T=25 °C, Concentration:40 mg/mL Hydrophobic interactions, Hydrogen bonding, Electrostatic repulsion, pH-regulated carboxyl dissociation Proposed a complete pH-responsive assembly model: partial dissociation forms fibers, and full protonation forms fiber bundles, full ionization forms spherical aggregates. ( Cai et al., 2025 ) Ultrafine semiflexible nanofibrils, Right-handed helical structure Diameter ≈ 2.5 nm, Pitch ≈ 9 nm pH = 3 - 5, Concentration > 0.3 wt%, Forms 3D network hydrogel at temperature < 55 °C Hydrophobic interactions, Hydrogen bonding, Chiral stacking GA nanofibers possess excellent gelation and interfacial and can be used to construct stable multiphase food systems. ( Li et al., 2022 ) Helical nanofibers formed by "Tail-to-Tail" dimer stacking SANS: Diameter 3.6 nm (core); SAXS: Diameter 4.2 nm (including shell) CAC = 0.22 ± 0.04 mM, CGC ≈ 2 mM, pH < pKa₃ (≈5.17) Hydrophobic interactions, Hydrogen bonding, Electrostatic interactions Proposed "tail-to-tail" core-shell model, confirmed as a kinetic stacking process rather than thermodynamic micellization. ( Trindade et al., 2025 ) Long nanofibers form a fibrous network structure Diameter ∼2.5 nm, Length long (micrometer scale) GA concentration > 0.1 wt%, Temperature: heated to 80 °C then cooled to 25 °C, pH not specified (weakly acidic conditions) Hydrogen bonding, Hydrophobic interactions GA nanofibers can form thermally reversible emulsion gels for edible oil structuring, with tunable mechanical properties and stability. ( Wan et al., 2017b ) Semiflexible nanofibers, Right-handed helical structure Diameter 2.5 nm, Period 9 nm GA concentration > 0.1 wt%, pH = 2 - 5, Temperature 25 - 60 °C Hydrogen bonding, Hydrophobic interactions GA nanofibers form thermally responsive supramolecular and can be used in various colloidal systems, such as emulsions, foams, and gel emulsions. ( Zhang et al., 2021 ) High-aspect-ratio nanofibrils, forming 3D fibrous network structure Fiber diameter ∼2.5 - 3 nm, Length up to micrometers, forming a porous gel network Temperature: Dissolved at 80 °C, gelation triggered by rapid cooling; Concentration: GA ≥ 0.5 wt% (minimum gelation concentration) Hydrogen bonding, Hydrophobic interactions, Chiral molecular stacking GA nanofibers form reversible gel networks via H-bonds, stabilizing bubbles and oil droplets in emulsion foams via interfacial multi-layer fiber shells and a continuous phase gel network, exhibiting temperature responsiveness (gel melting at 55-60 °C). ( Wan et al., 2018 ) Long nanofibers (fibrils) further form a fibrous network structure Fiber diameter ∼2.5 nm (AFM measurement) Concentration: ≥ 0.1 wt% forms fibers; ≥ 0.5 wt% forms hydrogel, Temperature: 25°C thermally reversible (gel-sol transition), Fibers are negatively charged (negative zeta potential) Hydrogen bonding, Hydrophobic interactions, Van der Waals forces, Electrostatic repulsion GA self-assembles in water to form nanofibers, further forming thermally reversible hydrogels; high fiber rigidity suits functional material construction. ( Wan et al., 2017a ) Ultra-long right-handed helical nanofibers, forming a nematic gel network Diameter: 2.5 nm, Pitch: 9 nm, Length: up to tens of micrometers Concentration: ≥ 0.025 wt% begins formation, ≥ 0.3 wt% forms transparent hydrogel, Temperature: Room temperature self-assembly, thermally reversible Hydrophobic interactions, Hydrogen bonding, Chirality transfer, π-π stacking GA can self-assemble in water into right-handed helical fibers of uniform and can construct GA-GO-AuNPs ternary hybrid hydrogels for catalysis. ( Saha et al., 2015 ) Single network hydrogel [27] Nanofiber width ∼2.5 nm, Length up to micrometers, Right-handed helical twist, Period of 9 nm Self-assembly in water; Temperature: heated to 80 °C to dissolve, gelation upon cooling Hydrophobic interactions, Hydrogen bonding, π-π interactions GA molecules can form supramolecular nanofibers via anisotropic self-assembly, further entangling to form hydrogels. ( Su et al., 2024 ) Physical hydrogel, based on GA self-assembled fibrous network forming "leaf-like" wall-like structure with cavities Cavity size 1.47 - 3.30 μm, Wall thickness 100 - 250 nm, Rheological parameters: Storage modulus G′: GA (5%) 38 kPa, GA (10%) 672 kPa (20 °C) Temperature: Gelation temperature 40 °C (GA=5%) and 48 °C (GA=10%); CAC: 5 - 10 wt%; GA dissolved in water Hydrophobic interactions, Hydrogen bonding, Van der Waals forces Pure GA can self-assemble in water to form thermally reversible physical hydrogels with significant mechanical strength; structure and properties can be effectively tuned by GA concentration. ( Mees et al., 2023 ) Single-component GA hydrogel / Minimum gelation concentration: 2%; GA dissolved in water Self-assembly of amphiphilic molecules (hydrophilic-hydrophobic balance) Single-component GA hydrogel is cytotoxic at high concentrations (≥2%), requiring metal ion regulation to reduce usage concentration. ( Qian et al., 2022 ) Supramolecular hydrogel composed of a 3D nanofiber network Nanofiber width ∼10 nm, Length hundreds of micrometers, Storage modulus G′: 30 - 90 Pa Concentration: 1.0% - 2.0%; Temperature: formed via heating/cooling cycles Hydrogen bonding, Hydrophobic interactions GA hydrogel exhibits significant shear-thinning behavior; the viscosity of 1.0% GA hydrogel at high shear rates is close to pure water, with similar atomization performance. ( Sun et al., 2022 ) interwoven nanofiber structure Nanofiber diameter ∼50 nm, Height ∼2 nm GA concentration: ≥ 0.3%; Temperature: room temperature (heated to dissolve, then cooled); pH range: 3 - 13 Hydrogen bonding, π-π stacking, Electrostatic interactions GA can spontaneously form stable hydrogels with injectability, adhesiveness, and pH responsiveness; suitable for rectal drug delivery. ( Lei et al., 2025 ) Filamentous fiber network Fibers are relatively fine GA concentration 15 mM (CGC = 12.3 mg/mL); In deionized water, heated to 80 °C, then cooled to room temperature Amphiphilic structure, Hydrophobic interactions, Hydrogen bonding GA can self-assemble to form hydrogels; Zn 2+ can reduce gelation concentration and enhance mechanical properties. ( Lu et al., 2024 ) Entangled fibrous structure Fiber average diameter ∼442 nm (SEM) PBS (pH = 7.4); Critical Gelation Concentration (CGC) = 6 mg/mL; Prepared by classical "repeated heating-cooling" method: heated to 85 °C, then cooled to 25 °C. Hydrogen bonding, Hydrophobic interactions GA can self-assemble to form stable hydrogels with injectability, self-healing, and adhesiveness; fiber structure is influenced by environmental conditions. ( Zeng et al., 2025 ) Open in a new tab 2.4.1. Morphological characteristics of nanofibers and hydrogels The final morphology of GA self-assemblies is highly dependent on environmental conditions, but a generally accepted structural model has now been established. Recent studies have confirmed that GA nanofibers are not simple rod-like micelles using SANS and cryo-TEM, but rather right-handed helical aggregates with a “core-shell” structure( Trindade et al., 2025 ). Their hydrophobic triterpenoid units are tightly packed via “tail-to-tail” interactions, forming a hydrophobic core with a diameter of approximately 3.6–4.2 nm; meanwhile, the hydrophilic diglucuronic acid groups extend outward to form a hydrated shell. The fibers exhibit a characteristic right-handed helical twist with a pitch of approximately 9 nm. When the GA concentration exceeds its CGC, typically around 2 mM or 0.2 wt%, these semi-rigid nanofibers form a viscoelastic three-dimensional network structure, a supramolecular hydrogel through physical entanglement and inter-fiber hydrogen bonding. This hydrogel network exhibits a porous structure, with a storage modulus (G') ranging from tens to thousands of pascals, demonstrating typical solid-like behavior ( Cai et al., 2025 ; Qi et al., 2023 ). Right-handed helical nanofibers and their resulting hydrogels represent the most stable higher-order assembly morphology of GA under weakly acidic conditions at appropriate concentrations. Notably, the formation of this fibrous network is highly selective for pH, achieving uniform fiber dispersion and transparent hydrogels only within the narrow window of pH 3-5, where moderate electrostatic repulsion balances hydrophobic interactions. Deviation from this pH range, whether due to excessively weak or strong electrostatic repulsion, leads either to lateral fiber bundling or to inhibited anisotropic growth, preventing the formation of an ideal fibrous network. This sensitivity necessitates strict control of environmental pH for applications involving GA hydrogels. 2.4.2. Formation conditions for GA self-assembly into nanofibers and hydrogels The process by which GA self-assembles into fibers and ultimately into gels is governed by both thermodynamic and kinetic factors. (1) CAC and Anisotropic Growth: The self-assembly of GA is not a classical micellization process. Instead, it is a kinetically controlled anisotropic growth process. When the GA concentration exceeds its CAC, molecules begin to stack from a monomeric or dimeric state to form nanofibers. Studies have shown that in pure water at 25°C, the CAC of GA is approximately 0.22 ± 0.04 mM. Above this concentration, dimers act as the basic building blocks and preferentially grow in one direction, forming one-dimensional fiber structures( Trindade et al., 2025 ). (2) CGC and Network Formation: As the GA concentration increases further, both the number and length of fibers in the system increase. When the concentration reaches the CGC, the entanglement and interactions between fibers are sufficient to form a continuous permeable network throughout the volume, causing the system to undergo a sol-gel transition, which manifests macroscopically as the formation of a viscoelastic hydrogel ( Baccile et al., 2021b ; Petrova et al., 2017 ). (3) pH: pH acts as a thermodynamic “switch” that determines the self-assembly pathway and final morphology. Modulating the dissociation of carboxyl groups, it alters the electrostatic repulsion between molecules, thereby influencing the balance between hydrophobic driving forces and hydrogen bond stabilization. When the pH is 3–5, the carboxyl groups are partially protonated; moderate electrostatic repulsion prevents disordered aggregation of the fibers, favoring anisotropic growth and the formation of discrete nanofibers, which subsequently entangle to form a transparent hydrogel. When pH < 3, the carboxyl groups are fully protonated, and electrostatic repulsion disappears. Hydrophobic interactions and inter-fiber hydrogen bonding become dominant, leading to lateral aggregation or bundling of fibers, resulting in a hydrogel with a microscopically heterogeneous and more turbid structure. When pH > 5.5–6, the carboxyl groups are highly deprotonated, and strong electrostatic repulsion inhibits hydrophobic-driven longitudinal stacking. At this point, anisotropic growth is disrupted, and the system tends to form thermodynamically more stable spherical aggregates or a monomeric solution, unable to form a fiber network ( Cai et al., 2025 ). (4) Temperature: Temperature primarily affects the stability of hydrogen bonds, which serve as the physical cross-linking points in the fiber network. At 25°C, hydrogen bonds are stable, and the network structure is robust. When the temperature rises above 55–60°C, the thermal energy is sufficient to break the hydrogen bonds between fibers, leading to network dissociation and a gel-sol transition in the hydrogel ( Li et al., 2022 ). This process is typically reversible; upon cooling, hydrogen bonds reform, and the network structure is restored ( Wan et al., 2018 ; Wan et al., 2017b ). This thermal reversibility confirms the physical cross-linking nature of the hydrogel. 2.4.3. Driving forces for GA self-assembly into nanofibers and hydrogels The formation of GA nanofibers and hydrogels results from the synergistic and competitive interactions of various noncovalent bonds, with driving forces operating at different levels. (1) Hydrophobic interactions: These are the core driving force behind self-assembly. In an aqueous environment, hydrophobic triterpenoid aglycones aggregate in a “tail-to-tail” manner to minimize their contact area with water, forming dimers and driving their longitudinal stacking to constitute the hydrophobic backbone of the nanofibers ( Trindade et al., 2025 ). (2) Hydrogen bonds: These are key to stabilizing the structure and forming the network. On one hand, polar groups on the aglycone and hydroxyl and carboxyl groups on the uronic acid form intermolecular hydrogen bonds, precisely guiding the helical stacking of the dimers (determining the 9 nm pitch) ( Wan et al., 2018 ). On the other hand, after fiber formation, the abundant sugar groups on the fiber surface interact with water molecules and adjacent fibers via hydrogen bonds, stabilizing the hydrophilic shell while forming physical cross-linking points between fibers, ultimately constructing a three-dimensional network. (3) Electrostatic interactions: These act as “regulators” of morphology and size. At different pH levels, the dissociation state of carboxyl groups directly determines the strength of the surface charge on the fibers. As mentioned above, moderate electrostatic repulsion (pH 3–5) is a necessary condition for forming a discrete ( Wan et al., 2017a ), uniform fiber network; the disappearance of repulsion leads to fiber aggregation, and excessive repulsion completely inhibits fiber formation ( Cai et al., 2025 ). 2.5. Hierarchical self-assembly and multistimulus-responsive transitions of GA ( Fig. 3 ) Fig. 3. Open in a new tab The schematic illustration of the GA self-assembly in dimer, micelles, nanoparticles, nanofibers, and hydrogels. The conditions (concentration, temperature, pH, ionic strength) and intermolecular forces affecting the GA self-assembly were illustrated. Moreover, the relevance among GA dimer, micelles, nanoparticles, nanofibers, and hydrogels was displayed. The self-assembly of GA is a dynamic hierarchical process that progresses from the molecular to the macroscopic level. As the most fundamental building block, the “tail-to-tail” hydrophobic core-shell structure of the dimer is stabilized by a combination of hydrophobic interactions and hydrogen bonding. When environmental conditions change, the assembly pathways of the dimers diverge. Under weakly acidic conditions (pH 3–5), hydrophobic interactions drive the dimers to stack in a one-dimensional helical fashion, forming nanofibers with right-handed helical characteristics; under strongly alkaline or hydrothermal conditions, electrostatic repulsion inhibits the anisotropic growth of the fibers, and the molecules instead aggregate to form thermodynamically more stable spherical nanoparticles; when the concentration exceeds the CMC, amphiphilic molecules can rearrange to form ellipsoidal or rod-shaped micelles. As the concentration further increases beyond the CGC, nanofibers with a high aspect ratio begin to entangle and form physical cross-linking points via abundant surface hydrogen bonds, ultimately constructing a hydrogel with a three-dimensional network structure. The most notable feature of this system is its multi-stimulus responsiveness. Elevating the temperature or raising the pH above 5 disrupts the hydrogen bond network or enhances electrostatic repulsion, causing the hydrogel to reversibly dissociate into a sol or micellar state; conversely, through heating-cooling cycles or adjusting the pH to acidic conditions, these dissociated states can reassemble into a fibrous network. This ability to undergo multi-path, reversible structural transformations makes GA an ideal platform for constructing smart, responsive materials. 3. Research on the application of GA in drug delivery 3.1. Formation of nanomicelles GA can self-assemble into nanomicelles with other hydrophobic drugs in water ( Cui et al., 2024 ), which remarkably enhances the solubility, bioavailability, and stability of the latter ( Yang et al., 2015 ; Yang et al., 2024 ). These carriers also facilitate targeted drug delivery and reduce toxicity to normal skin tissues ( Cai et al., 2019 ). 3.1.1. Co-assembly mechanisms GA forms stable micelles with various drugs through hydrophobic interactions and hydrogen bonding. Its triterpenoid hydrophobic core encapsulates the aromatic rings or the nonpolar groups of drug molecules, while hydroxyl groups on the sugar chain form hydrogen-bonded networks with the drugs. This self-assembly process typically occurs at 37–50°C. Excessively high temperatures disrupt intermolecular forces, while low temperatures hinder micelle formation. Moreover, the optimal assembly is achieved at a GA concentration of 1–10 mM. Under weakly acidic conditions (pH 5–6), the carboxyl group of GA undergoes moderate ionization, maintaining micelle stability without excessive dissociation. Therefore, the self-assembly process is predominantly regulated by temperature, concentration, and pH. Temperature primarily affects molecular motion, whereas concentration determines micelle formation, and pH controls ionization equilibrium ( Table 5 ). Table 5. The preparation conditions for GA-Drug composite nanoparticles Encapsulated Drug Intermolecular Interactions Assembly Temperature Concentration Conditions pH Conditions References rePaclitaxe Hydrophobic interaction, Hydrogen bonding, π-π stacking 45-50°C GA:PTX = 10:1 (w/w) GA concentration: 10 mM Neutral (pH 7.4) ( Yang et al., 2015 ) Hydroxycamptothecin Hydrophobic interaction, Hydrogen bonding, Electrostatic interaction 45°C HCPT solubility is optimal when GA concentration is 40-60 mg/mL Maintains stable HCPT lactone form at pH 3-5 ( Cai et al., 2019 ) Licochalcone A Hydrophobic interaction, Hydrogen bonding 65°C GA:LicA = 8:1 (mass ratio) Not specified, but PBS buffer (pH 7.4) was used ( Wang et al., 2022a ) Cantharidin (CTD) Disulfide bond, Hydrophobic interaction, Hydrogen bonding 50°C Cell uptake is optimal when F127-GA accounts for 10-15% 7.4 ( Hu et al., 2024 ) Baicalein Hydrophobic interaction, Hydrogen bonding 37°C GA:BE = 10:1 (molar ratio) GA concentration: 10 mM 6.8 / 8.3 ( You et al., 2021 ) Evodiamine Encapsulated within a hydrophobic core 37-40°C GA 40 mg/mL Not adjusted (natural pH) Berberine Electrostatic interaction, Hydrogen bonding 60-80°C Berberine:GA = 1:1 (molar ratio) Weakly acidic (pH 3.9-7.4) ( Qiao et al., 2025 ) Matrine Hydrophobic interaction, Hydrogen bonding 80°C Matrine:GA = 1:2 (molar ratio) Neutral (pH 7.4) ( Qiao et al., 2025 ) Paeoniflorin Hydrophobic interaction, Hydrogen bonding 50°C GA: 4 mg/mL, Pae: 1 mg/mL 7.4 ( Shen et al., 2021 ) Curcumin Hydrophobic interaction, Hydrogen bonding, π-π stacking 37°C GA concentration 0.5-3 wt% forms gel ( Section 3.3 ) 7.4 ( Piao et al., 2022 ) Podophyllotoxin (POD) Hydrophobic interaction 60°C GA/POD mass ratio of 8:1 Sustained-release characteristics at pH 7.4 ( Wang et al., 2016 ) Curcumin (Cur) Hydrophobic interaction and Hydrogen bonding 37°C GA concentration ≥ 0.5 wt% Neutral (pH 7.4) ( Zheng et al., 2023a ) Open in a new tab 3.1.2. Drug delivery systems formed by GA monomer carrier ( Table 6 ) Table 6. The micellar structures, pharmacokinetic improvement, aqueous solubility enhancement of different drugs encapsulated by GA micelles Drug Name Pre-encapsulation Properties Micelle Size (nm) Micelle Morphology Pharmacokinetic Improvement Skin Permeability Aqueous Solubility Enhancement Post-encapsulation Type References Paclitaxel (PTX) Poor water solubility 245.4 ±5.6 Spherical nanoparticles AUC₀→24h increased 6-fold Significantly enhanced (1.27-fold) ∼1000-fold GA Micelles ( Yang et al., 2015 ) Hydroxycamptothecin (HCPT) Poor water solubility, poor stability 105.7 ±9.7 Spherical AUC₀-t reached 442.8 μg/L*h Not Applicable From nearly insoluble to 31.3 μg/mL GA-HCPT Micelles ( Cai et al., 2019 ) Cryptotanshinone (CTS) Poor water solubility, low skin permeability 24.81 ±1.40 Uniform spherical AUC significantly increased, swelling volume reduced by 80.1% Significantly improved Factor not specified GA-CTS Micelles ( Liang et al., 2025 ) ( Fig. 4 ) Podophyllotoxin (POD) Poor water solubility, significant skin irritation ∼10 Spherical Sustained release (zero-order kinetics) Permeation rate increased 2.26-fold 48-fold GA-POD Micelles ( Wang et al., 2016 ) Emodin (Emo) Poor water solubility, colon toxicity 168.64 ±5.69 Spherical Excretion rate increased (ER=1.24) Not Applicable From nearly insoluble to detectable concentration GA-Emo Micelles ( Wang et al., 2024 ) Curcumin (CUR) Hydrophobic 86.33 ±2.9 Spherical Sustained release for 8 days Not Applicable 96% solubility GA-Cur Micelles ( Zheng et al., 2023a ) Paeoniflorin (Pae) Poor water solubility 58.89 ±4.24 Spherical AUC increased 3.64-fold Not studied Not specified GA-PAE Micelles ( Shen et al., 2021 ) Licochalcone A (LicA) Poor water solubility 31.38 ±0.42 Spherical Skin retention increased 16.2-fold Primarily permeates via the follicular pathway Significantly increased GA Self-assembled Micelles ( Wang et al., 2021 ) ( Fig. 5 ) Linoleic Acid (LA) Hydrophobic, easily oxidized 31.38 ±0.42 Spherical Skin retention increased 16.2-fold Enhanced epidermal and dermal penetration Significantly improved GA Self-assembled Micelles ( Su et al., 2024 ) Crocin Poor water solubility, susceptible to heat, oxygen, light, and acidic environments ∼200 (self-assembled) Vesicular Significantly increased Cmax and AUC Primarily permeates via the follicular pathway 1212-fold Mixed Micelles ( Su et al., 2024 ) Open in a new tab The self-assembly of hydrophobic drugs with GA is driven primarily by intermolecular hydrophobic interactions, hydrogen bonding, π-π stacking, and electrostatic stabilization mechanisms ( Zeng et al., 2025 ). The triterpenoid aglycone moiety in GA molecules forms a hydrophobic core, effectively encapsulating lipophilic drug molecules, while the glucuronic acid groups constitute a hydrophilic shell that maintains micelle stability in aqueous phases ( Zhao et al., 2024b ). This self-assembly process typically achieves optimal equilibrium at drug-to-GA molar ratios of 1:2–1:4. GA can enhance the oral bioavailability of drugs, such as paeoniflorin and evodia. Shen et al. ( Shen et al., 2021 ) developed a GA-paeoniflorin micelle system with a GA: paeoniflorin ratio of 5:1 (w/w), yielding stable micelles with a particle size of 58.89 nm. This system significantly enhanced paeoniflorin's oral bioavailability by inhibiting intestinal P-glycoprotein efflux and first-pass metabolism, increasing the area under the concentration-time curve (AUC) by 3.64-fold. More importantly, GA and paeoniflorin synergistically inhibit inflammatory mediators and modulate T-cell subsets for treating autoimmune diseases. Qiao et al. ( Qiao et al., 2025 ) investigated the anti-ulcerative colitis (UC) effects of naturally self-assembled berberine-GA and matrine-GA complexes in Qingchang wenzhong Decoction. Isothermal titration calorimetry (ITC) revealed strong binding affinities between GA and alkaloids (BER: Kd=2.55×10 -4 M; MAT: Kd=6.77×10 -4 M), primarily driven by charge transfer and hydrogen bonding interactions. Compared to free alkaloids, BER-GA and MAT-GA complexes exhibited stronger anti-inflammatory effects in RAW264.7 cells by significantly inhibiting pro-inflammatory cytokines (including TNF-α, IL-1β, IL-6) and upregulating anti-inflammatory cytokines. Deng et al. constructed evodiamine-GA (EVO-GA) micelles to enhance anti-liver fibrosis effects. Researchers prepared micelles with a particle size of 130.80±12.40 nm, a zeta potential of -41.61±3.12 mV, an encapsulation efficiency of 91.23%, and a drug loading capacity of 8.42% using the thin-film dispersion method. EVO-GA demonstrated synergistic anti-fibrotic effects, significantly reducing liver function indicators in fibrotic rats, with therapeutic efficacy markedly superior to that of the free drugs. In topical applications, the self-assembly of GA with hydrophobic drugs remarkably enhances the water solubility and transdermal efficiency of the payloads. Wang et al. ( Wang et al., 2022a ) developed a GA-LicA micelle system to investigate cellular uptake mechanisms and bioavailability enhancement. GA-LicA micelles exhibited a particle size of 31.38 ± 0.42 nm, which increased LicA skin penetration by 12.86-fold, with hair follicles as the primary penetration pathway. Cellular experiments revealed uptake rates of 96.52% and 98.17% for HaCaT cells and melanocytes, respectively, in which clathrin-mediated and other endocytic pathways played crucial roles in cellular uptake. Liu et al. ( Liu et al., 2025a ) developed a novel nanodelivery system (PGNs) based on the self-assembly of GA and paclitaxel (PTX), enhancing PTX solubility by nearly 400-fold and transdermal efficiency by 2–8-fold. Wang. prepared GA-LA micelles with a particle size of 36.00±2.601 nm via solvent evaporation and demonstrated their epidermal targeted delivery via the follicular pathway ( Li et al., 2023c ). The co-permeation mechanism indicated that 9.32% intact micelles permeate through the SC via the follicular pathway in 24 h, followed by dissociation within the skin layers to release free drug. In vitro experiments demonstrated that these micelles reduced tyrosinase activity by 2.3-fold ( Fig. 4 ). Moreover, a UVB-induced pigmentation model confirmed synergistic whitening effects of GA and LA without skin irritation. Wang et al. ( Wang et al., 2025c ) further demonstrated that these GA-LA binary co-assembled nanoparticles (BCGNs) could be incorporated into ovalbumen-based supramolecular hydrogels, achieving enhanced drug release and superior anti-inflammatory efficacy in acute inflammation management compared to hydrogels lacking either component. Fig. 4. Open in a new tab Visualization of GA and LA co-penetration pathways in rat skin using CLSM [74]. (a) Confocal microscopy reveals GA (green) presence in hair follicles (white arrows) and intercellular spaces (pink arrows) of rat skin over 24 h post-treatment with GA+NB-LA micelles or a GA-LA solution. NB-LA micelles show sustained GA presence, suggesting enhanced penetration. (b) NB-labeled GA+NB-LA micelles (red) penetrate viable epidermis (merged with DAPI-stained nuclei, blue) within 6 h, accumulating further by 24 h. Free LA (green) is largely confined to the stratum corneum at earlier time points. Scale bar = 100 μm. Reproduced with permission from Z. Wang, Y. Xue, T. Chen et al., "Glycyrrhiza acid micelles loaded with licochalcone A for topical delivery: Co-penetration and anti-melanogenic effect," Eur. J. Pharm. Sci., 2021, 167, 106007, DOI: 10.1016/j.ejps.2021.106007. Copyright 2021, Elsevier. Compared to oral and topical administration, injection offers a more direct pathway for precise drug targeting and rapid onset of action. Cai et al. ( Cai et al., 2019 ) constructed GA-hydroxycamptothecin (GA-HCPT) micelles for injection to enhance antitumor activity. The spherical micelles exhibited an average diameter of 105.7±9.7 nm, achieving a drug loading capacity of 9.0±1.5%. These micelles were rapidly internalized by HepG2 cells, significantly increasing HCPT accumulation in the cells. Compared to commercially available HCPT injection, GA-HCPT micelles exhibited stronger antitumor activity against hepatocellular carcinoma cells (HepG2 and Huh7) and tumor growth in HepG2-bearing mice. GA-HCPT micelles primarily accumulated in the liver, which reduces drug accumulation in normal tissues, resulting in minimal cytotoxicity toward normal human hepatocytes (LO 2 ). Based on the above, when poorly soluble drugs are encapsulated by GA, nanomicelles demonstrated particle sizes ranging from approximately 10 nm to 245 nm. In most systems, the micelle morphology is predominantly regular spherical, with isolated cases of porous sponge-like or branched fiber networks. Following GA encapsulation, the water solubility of drugs generally increased significantly, with enhancement efficiency usually exceeding 100-fold. In transdermal delivery systems, the skin permeation enhancement ranges from 1.27-fold to 12.8-fold. Pharmacokinetically, the bioavailability of encapsulated drugs is effectively improved, with AUC typically increasing by more than 2-fold and up to approximately 6-fold. As a result, the drug half-life is prolonged, and clearance is reduced, demonstrating favorable sustained-release and retention properties in vivo. 3.1.3. Drug delivery systems formed by GA and other carrier-loaded drugs In recent years, a series of multifunctional composite nanodelivery platforms have been developed by combining GA with metal ions (e.g., Cu 2+ ), natural polyphenols (e.g., protocatechuic acid), polysaccharides (e.g., inulin), and bio-derived carriers (e.g., exosomes). ( Table 7 ) These systems not only significantly enhance the solubility and targeting of poorly soluble drugs (e.g., pyrimethamine, curcumin, tanshinone IIA) but also generate synergistic therapeutic effects with the loaded drugs. For instance, the GA-Cu 2+ coordination network mimics the SOD-CAT enzyme cascade to efficiently scavenge ROS ( Jia et al., 2025 ), while the assembly of GA and polysaccharides confers colonic microbiota-responsive precision drug release. This “carrier-drug-bioactive compound” trinity design strategy offers solutions for treating infectious diseases, tumors, and chronic inflammation. Hu et al. ( Hu et al., 2024 ) constructed cantharidin-GA hybrid micelle systems. Moreover, a nanocapsule copolymer composed of GA and pluronic F127-disulfide bond_poly (lactic acid) was established with a diameter of 85.17 nm. The introduction of redox-sensitive disulfide bonds into this delivery system enables specific dissociation of the micelles under high glutathione concentrations in the tumor microenvironment, achieving targeted drug release. In vitro experiments demonstrated that these micelles could enhance cantharidin cellular uptake by 3.2-fold while significantly reducing toxicity to normal hepatocytes. Wang et al. ( Wang et al., 2025b ) combined GA with oxymatrine (OMT) to prepare ionic liquids at a molar ratio of 1:3 through N + -O - and -COOH ionic hydrogen bonds. This system was further self-assembled into micelles with a particle size of 15.377 nm in aqueous solution without additional excipients, which is capable of enhancing the solubility of palmitoyl pentapeptide-4 (PAL-4) by 20-fold. In vitro permeation tests revealed that 10% GAO-SM increased the cumulative permeation of PAL-4 by 5.64-fold, which enhanced permeability by regulating SC lipid arrangement. In photoaging models, GAO/PAL-4-SM significantly promoted collagen I and hyaluronic acid regeneration while suppressing TNF-α and IL-6 expression ( Fig. 5 ). The EXO-GA-TanIIA micelle (CpG-EXO/TGM) innovatively leveraged the natural targeting properties of exosomes (EXO), increasing brain drug accumulation by 2.74-fold. GA blocks tumor immune evasion by inhibiting STAT3 phosphorylation, while CpG ODN activates the TLR9 pathway to induce DC maturation. This dual mechanism nearly doubled survival in glioma mice ( Cui et al., 2023 ). GA-CUR-inulin system (CURG@IN) achieves colon-specific drug release via inulinase activation, while GA inhibits the NF-κB pathway. Inulin promotes the proliferation of beneficial bacteria like Muribaculaceae, which reconstitutes the “gut barrier-microbiota-immune” homeostasis, reducing DAI scores by 64% in colitis mice ( Li et al., 2023b ). Table 7. The micellar structures, pharmacokinetic improvement, aqueous solubility enhancement of different drugs encapsulated by GA micelles with other carriers. Micelle Name Composition Micelle Size (nm) Pharmacokinetic Improvement Skin Permeability Enhancement Aqueous Solubility Enhancement Factor Post-encapsulation Type Micelle Morphology References GA-CG-K Micelles GA+ Cu 2+ + Polysaccharide (CG) 15.2 ± 2.3 Sustained release behavior (pH 2.5: 60%; pH 7.5: rapid release) / / GA-CG Hydrogel Dual-network structure ( Yu et al., 2024 ) GAO-SM Micelles GA + OMT 15 / Significantly enhanced (10% GAO-SM) >20-fold GAO ILs Self-assembled Micelles Spherical core-shell structure ( Jia et al., 2025 ) CpG-EXO/TGM GA+ Tanshinone IIA (TanIIA) + EXO 15 Prolonged circulation time BBB penetration enhanced (TfR-mediated) N/A EXO-encapsulated GA-TanIIA Micelles Spherical, core-shell structure ( Cui et al., 2023 ) CURG@IN Micelles GA+ CUR + Inulin (IN) 83 / / Significantly improved IN Hydrogel-loaded CURG Nanoparticles Spherical ( Wu et al., 2025a ) PamHRchol/GA mixed micelles Cholesterol-conjugated PamHR (PamHRchol) +GA 107.1 Higher gene delivery efficiency than PEI25k and PamHRchol micelles / Significantly improved transfection efficiency for intracellular gene delivery. Forms stable pDNA complexes Spherical nanoparticles ( Choi et al., 2021 ) AE-M (Aloe Emodin-loaded mixed micelles) Soluplus® + GA + Aloe Emodin (AE) 30.13 ± 1.34 Relative oral bioavailability increased 3.09-fold compared to free AE / Solubility significantly increased from 0.51±0.01 μg/mL Forms stable nanocomplexes Uniform spherical ( Shi et al., 2022 ) Open in a new tab Fig. 5. Open in a new tab The mechanisms underlying GA enhancing PAL-4 permeation [79]. (a) Infrared spectra and (b) DSC thermograms of porcine skin treated with PAL-4 or GAO/PAL-4-SM for 24 h. (c) 2D docking models of interactions between keratin residues and OMT (black arrows mark N + -O - bonds). (d) Minimum energy conformations of ternary complexes formed by GA, OMT, and different SC lipids (FFA, Cer, or CHO). (e) Mixing enthalpies of GA with various SC lipids. (f) 13 C NMR spectra of ceramide before/after co-treatment with GA or OMT. (g) Interaction networks between SC lipids, keratin, GA, and OMT based on 13 C NMR analysis. Reproduced with permission from Z. Wang et al., "Bioactive Glycyrrhizic Acid Ionic Liquid Self-Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti-Photoaging Signal Peptides," Adv. Sci., 2025, 12, 8, 2412581, DOI: 10.1002/advs.202412581. Copyright 2025, Wiley-VCH GmbH. 3.2. GA-based composite nanocarriers for enhanced drug delivery GA-based nanofiber systems demonstrate unique therapeutic advantages. In oral cancer treatment, GA was co-loaded with the chemotherapy drug methotrexate into hyaluronic acid nanofibers, creating a local delivery system. This system enables targeted delivery of chemotherapy drugs and reduces systemic toxicity, leveraging GA's inherent anti-inflammatory properties to effectively alleviate chemotherapy-induced oral mucositis. Animal studies demonstrated that this delivery system significantly reduced tumor volume and induced apoptosis rates as high as 63.97% in oral squamous cell carcinoma cells ( Halder et al., 2024 ). Cao et al. ( Cao et al., 2023 ) prepared EG@EMHM NPs by fusing red blood cells and macrophages to form an engineered membrane (EMHM), then encapsulating emodin and GA. The results revealed that GA significantly enhanced emodin solubility. EG@EMHM NPs exhibited an average particle size of 170±20 nm with an encapsulation efficiency of 98.13±0.67%. Photodynamic therapy (PDT)-mediated EG@EMHM NPs significantly enhanced emodin solubility and demonstrated potent antitumor effects against melanoma via the BAX and BCL-2 pathways. Hanna Salminen et al. ( Salminen et al., 2022 ) investigated the influence of GA on the formation and stability of Glyceryl Tristearate solid lipid nanoparticles (SLN). The study revealed that GA enables the formation of nanoscale SLNs at both pH 7 and pH 3, stabilizing SLNs against polymorphic transitions. At pH 7, GA acts as a template to induce SLN crystallization via heterogeneous nucleation; whereas at pH 3, SLNs crystallize through homogeneous nucleation. Both GA concentration and pH jointly influence crystallization behavior and physical appearance, with high concentrations effectively reducing polymorphic transitions in tris(2-hydroxypropyl)glycerol stearate crystals. Kamath et al. ( Wang et al., 2018 ) demonstrated that nanoparticles (GA-EA NPs) formed by GA with ovalbumin (EA) significantly enhance the oral bioavailability of ibrutinib (IBR). IBR-GA-EA NPs exhibit an average particle size of 194.10±2.59 nm, polydispersity index (PDI) of 0.22, zeta potential of -33.96 mV, and encapsulation efficiency of 82.88%. In vitro release studies demonstrated superior sustained-release properties compared to the free drug. Pharmacokinetic studies revealed that the oral bioavailability of IBR-GA-EA NPs and IBR-GA-COMP was 3.21-fold and 3.41-fold higher than that of IBR suspension, respectively. Moreover, the solubility of IBR is enhanced by 7.22-fold at a 20 mM GA concentration. Wu et al. ( Wu et al., 2017 ) demonstrated that GA-conjugated human serum albumin nanoparticles encapsulating resveratrol (GA-HSA-RES-NPs) significantly enhanced resveratrol's bioavailability and liver targeting. They were prepared using high-pressure homogenization emulsification, yielding an average particle size of 108.1±5.3 nm, polydispersity index (PDI) of 0.001, and a GA-HSA coupling amount of 112.56 μg/mg. Drug encapsulation and loading efficiencies were 83.6% and 11.5%, respectively. In vitro release experiments demonstrated that GA-HSA-RES-NPs exhibited slow and sustained release characteristics. 3.3. GA self-assembled hydrogels as hydrogel drug delivery scaffold The assembly of GA hydrogels primarily relies on molecular self-organization, which forms higher-order structures. This process begins with GA spontaneously aggregating through noncovalent interactions to form nanofiber building blocks. For instance, GN-BR hydrogels are constructed through hydrogen bonding, hydrophobic interactions (as the initial driving force for fiber formation), and dynamic covalent bonds (e.g., Schiff base bonds). GA nanofibers and their interactions with BR molecules, forming aggregated fiber networks embedded within GN-BR particles ( Li et al., 2025b ). Metal ions like Zn 2+ could promote GA self-assembly through coordination interactions and lower the critical gelation concentration. The synergy and balance of these intermolecular interactions determine the macroscopic properties of hydrogels, such as the mechanical strength, the self-healing and injectability, and the stability and low swelling ( Qin et al., 2025 ). 3.3.1. GA-based single/multi-carrier drug-loaded hydrogels By binding with other active molecules or polymers, GA could form structurally stable, functionally diverse hydrogel systems ( Table 8 ). Its exceptional versatility and functionality in hydrogel construction enable the formation of injectable, self-healing and even smart responsive gel networks through self-assembly or crosslinking with polymers, such as chitosan and sodium alginate. At the microscopical level, these hydrogels typically exhibit porous fibrous or sponge-like structures. GA-based carrier systems can sensitively respond to physiological environmental changes. For instance, under specific pH or temperature conditions, they enable precisely regulations of drug release behavior, thereby sustaining release and targeted delivery to different sites. Table 8. Characteristics of drug carriers (Hydrogels) based on GA systems. Drug/Active Ingredient GA Construction System Hydrogel Type Morphological Characteristics Key Physicochemical Properties Drug Release Characteristics references Thymol (THY) GA Self-assembly Injectable, pH-responsive Porous sponge-like structure (pore size 5-30 μm) Swelling ratio 455-37% (pH-dependent) Sustained release of THY (99.75% encapsulation efficiency) ( Cui et al., 2024 ) Gallic Acid GA Self-assembled Hydrogel Metal ion-crosslinked hydrogel Uniformly distributed pores Rapid gelation, increased storage modulus (G'), and self-healing ability Sustained release characteristics ( Zhang et al., 2024 ) Pseudoephedrine (PE) Hydrogen-bonded assembly with GA Thermosensitive Spherical nanoparticles (size 552.6 nm) Phase transition temperature 65°C Intestinal release 69.5% ( Yang et al., 2025 ) Sinomenine (SIN) Electrostatic assembly with GA Injectable, Self-healing Nanofiber network (length > 10 μm) Adhesion force 22 N/m 50% release in 24 h ( Jiang et al., 2025 ) Puerarin (PUE) Co-assembly with GA Antibacterial, dual-component Helical fiber structure (d-spacing 2.24 nm) Selective anti- S. aureus Temperature-triggered release ( Zeng et al., 2025 ) Cryptotanshinone Derivative (CU) GA-Peptide Conjugate Co-assembled Interwoven nanofibers (diameter 50-100 nm) Self-healing time < 30 s Skin permeation increased 1.4-fold ( Zeng et al., 2025 ) Berberine (BBR) GA-BBR Hydrogel Self-assembled nanofiber hydrogel Interwoven nanofibers (diameter 50 nm, height 2 nm) Excellent injectability and adhesiveness, pH-responsive Tolerates acidic environment at pH 1.5, sustained release up to 140 h at pH 4.5 ( Qian et al., 2022 ) Curcumin (Cur) GA@Cur Micelle Hydrogel Micelle-hydrogel composite system Spherical micelles (diameter ∼75 nm) Shear-thinning behavior, self-repairing ability, thermoresponsive 85% Curcumin released in 72 h, faster release at pH 7.4 than at pH 4.5 ( Lei et al., 2025 ) Genkwanin (GK) GA Nanofiber Network Dual-component co-assembled hydrogel Interwoven nanofiber network structure Thermosensitive (gel-sol transition at 65°C) Sustained release (release rate < 50% in 24h) ( Yang et al., 2023 ) Amygdalin (AMY) AG-gel (AMY/GA) All-natural bioactive ingredient hydrogel Honeycomb-like 3D network structure (SEM shown) Excellent injectability, self-repairing ability, and modulus matching brain tissue Rapid degradation (degradation rate > 80% within 22 h), rapid release of active ingredients ( Luo et al., 2025 ) Ephedrine (EPH) GA nanofiber network co-assembled with EPH via hydrogen bonding and hydrophobic interactions. Dual-component co-assembled nanogel Interwoven nanofiber network structure Thermosensitive, pH-responsive At pH 1.2, EPH releases 79.41%, GA releases 9.79%; at pH 7.8, both release rates are ∼85% ( Song et al., 2024 ) Open in a new tab In the context of oral administration, Yang et al. ( Zeng et al., 2025 ) discovered that GA and puerarin (PUE) form a dual-component hydrogel nanofiber network driven by hydrogen bonding. This hydrogel demonstrated outstanding self-healing properties and superior inhibitory effects against Staphylococcus aureus . Similarly, Wu et al. ( Yang et al., 2025 ) developed a smart hydrogel self-assembled by pseudoephedrine (PE) and GA, which effectively modulates the Hsp90/NF-κB signaling pathway. Animal experiments confirmed that oral administration of this hydrogel significantly suppressed neutrophil hyperactivation, exerting sustained antipyretic effects. In another study, Zhang et al. ( Jiang et al., 2025 ) demonstrated that stachydrine (SIN) and GA hydrogel alleviated rheumatoid arthritis symptoms by inhibiting NF-κB and MAPK signaling pathways. This approach reduced joint inflammation scores, decreased the production of pro-inflammatory cytokines and improved joint function. For topical drug delivery, Li et al. ( Li et al., 2023a ) demonstrated that a dual network hydrogel compression of GA and sodium alginate (ALG) exhibits pH-responsive release properties. The hydrogel releases drugs significantly faster under alkaline conditions (pH 7.5) compared to acidic conditions (pH 2.5), making it suitable for topical skin administration. Chen et al. ( Wu et al., 2024 ) designed a GA-based hydrogel specifically for burn wounds. Mostafa Saeedi et al. ( Saeedi et al., 2023 ) developed a chitosan/glycyrrhetinic acid hydrogel with a swelling ratio ranging from 455–37% across a pH range of 4–7, indicating good compatibility with skin. Zhang et al. ( Zhang et al., 2024 )proposed a (Ga/GA) hydrogel based on GA and gallium (Ga) ions for treating pressure ulcers infected with multidrug-resistant Pseudomonas aeruginosa (MRPA). Their study revealed that the Ga/GA hydrogel forms an interpenetrating polymer network induced by Zn 2+ , exhibiting remarkable antibacterial performance and satisfactory biocompatibility. The hydrogel significantly reduced the M1/M2 macrophage ratio, promoted wound healing, and achieved a 91% wound healing rate within 14 days. Qian et al. ( Qian et al., 2022 ) developed a photo-enhanced GA-methacrylated sericin (SFMA) hybrid hydrogel (SF/GA/Zn) for diabetic wound treatment. The hydrogel forms a dual-network structure simultaneously induced by Zn 2+ and photo-crosslinked by SFMA, which effectively modulates macrophage polarization toward the M2 phenotype. The SF/GA/Zn hydrogel markably accelerated all three stages of diabetic wound healing, achieving a 91% healing rate within 14 days while reducing the expression of pro-inflammatory factors. Additionally, Wang et al. ( Guo et al., 2025a ) developed a novel injectable GA hydrogel that effectively promoted acute wound healing and tissue regeneration. Li et al. ( Li et al., 2023b ) designed an aldehyde-containing GA/carboxymethyl chitosan hybrid hydrogel with excellent injectability and shape adaptability. This hydrogel is effective in promoting healing in full-thickness skin wounds and Staphylococcus aureus-infected wounds. For acne treatment, Zeng et al. ( Zhao et al., 2024b ) developed a co-assembled hydrogel of cryptotanshinone derivatives and GA, which exhibits shear thinning and thixotropic recovery properties. Molecular dynamics simulations revealed assembly mechanisms involving hydrogen bonding, π-π stacking, and electrostatic interactions. This hydrogel not only effectively inhibited Propionibacterium acnes, Staphylococcus aureus, and Escherichia coli but also promoted the healing of MRSA-infected skin wounds. Yang et al. ( Yang et al., 2023 ) demonstrated that self-assembly hydrogels formed from glycyrrhetinic acid and guanaholic acid (GK) effectively inhibited 4T1 breast cancer growth and lung metastasis by modulating the CXCL1/2-S100A8/9 signaling axis. Wang et al. ( Yang et al., 2023 ) developed a novel hydrogel (GBR-gel), which was self-assembled by GA, copper ions (Cu 2+ ), and luteolin (Lyc), exhibiting excellent drug loading capacity and biocompatibility. GBR-gel effectively induces copper-mediated cell death in tumor cells, manifested by downregulation of ferritin FDX1 and LIAS expression. Meanwhile, it triggers PAN apoptosis through massive ROS production and activating key proteins, including Caspase-3, Caspase-1, and MLKL. Yuan et al. ( Yuan et al., 2024 ) explored another interpenetrating network, using alloy nanoenzyme-enhanced hyaluronic acid. This system forms a multi-crosslinked structure through the self-assembly network of catechol-modified hyaluronic acid and GA, combined with zinc-doped hollow mesoporous ceria-induced metal-polyphenol coordination. It promotes cell migration, angiogenesis, and macrophage polarization toward an anti-inflammatory phenotype in vitro. Luo et al. ( Luo et al., 2024 ) demonstrated GBR-gel self-assembled by GA, berberine, and emodin, which displayed superior neuroprotection and anti-inflammatory effects in traumatic brain injury models. This gel forms spontaneously under physiological conditions without exogenous carriers, exhibits excellent biocompatibility and brain-tissue-matched mechanical properties, and promotes oligodendrocyte precursor cell differentiation and myelin regeneration by regulating glutamatergic synaptic pathways. It effectively alleviates cerebral edema, suppresses inflammatory responses, and facilitates neural function recovery, offering a novel strategy for localized precision treatment of TBI. 3.3.2. GA metal-coordinated hydrogels Hydrogel systems based on the coordination of GA with metal ions offer numerous advantages. By employing natural molecules as building blocks, these systems enable the fabrication of multifunctional materials through a straightforward, environmentally friendly “one-pot” approach that eliminates the need for external carriers. This system integrates excellent injectability with self-healing capabilities, enabling precise filling and tight adhesion to irregular tissue cavities through injection. ( Pi et al., 2023 ). ( Table 9 ) (See Table 10 .) Table 9. Characteristics of hydrogels formed by metal-coordinated hydrogel. Drug/Active Ingredient GA Construction System Hydrogel Type Morphological Characteristics Key Physicochemical Properties Drug Release Characteristics References GA, Copper Ion (Cu 2+ ), Protocatechuic Acid (PA) Self-assembly System Self-assembled Hydrogel Spherical Morphology pH-responsive, Self-healing pH-responsive Release ( Jia et al., 2025 ) GA, Copper Ion (Cu 2+ ), Catechol Interpenetrating Network System Interpenetrating Network Hydrogel Porous Network Structure Enhanced Mechanical Properties, Adhesiveness Sustained Release ( Yuan et al., 2024 ) GA, Copper Ion (Cu 2+ ), Lycorine (Lyc) Three-component System Three-component Hydrogel Porous Reticular Structure Thermosensitive, Injectable Sustained Release ( Wu et al., 2025b ) GA, Copper Ion (Cu 2+ ), Celastrol (Cel) Three-component Carrier-free System Three-component Carrier-free Hydrogel Spherical Particles Injectable, Self-healing On-demand Release ( Luo et al., 2024 ) Open in a new tab Table 10. The permeation-enhancing effect of GA on different drugs. Encapsulated Drug Permeation Enhancement Ratio Solubilization Ratio Pharmacokinetic Parameters References Paclitaxel (PTX) 6-fold (intestinal absorption) 200-fold (0.67 → 124 μg/mL) AUC0-24h increased 6-fold (0.573 → 3.42 μg·h/mL), Cmax increased 4.8-fold (0.095 → 0.460 μg/mL) ( Yang et al., 2015 ) Praziquantel (PZQ) 3-4 fold (membrane permeability) 1.5-fold (0.81 → 1.2 mM) Bioavailability improved 3-fold, therapeutic dose reduced 10-fold ( Kim et al., 2019 ) Ibrutinib (IBR) 3.21-3.41 fold 7.29-8.67 fold ( in vitro release) AUC0-48h increased 3.21-3.41 fold, Cmax increased 3.3-4.5 fold ( Kamath et al., 2024 ) Carvedilol (CDL) 3-fold (transdermal absorption) 59-fold (in buffer solution) Transdermal delivery of controlled hypertension for up to 28 h ( Sapra et al., 2008 ) Cantharidin (CTD) Significantly enhanced cellular uptake Drug Loading Capacity: 16.12% Exhibited excellent cytotoxicity and apoptosis-inducing ability ( Hu et al., 2024 ) Lycorine (Lyc) Significantly improved tumor accumulation Achieved 100% Drug Loading Capacity In vivo anti-tumor effect was significantly superior to free Lyc ( Wang et al., 2025a ) Podophyllotoxin (POD) Not explicitly quantified POD solubility increased from 0.104 mg/mL (water) to 5 mg/mL (GA solution) Skin Deposition: POD-GA Micelle Group (24.37 μg/cm 2 at 12h) was higher than POD Tincture Group (20.07 μg/cm 2 ) ( Yamashita et al., 2017 ) Hydroxycamptothecin (HCPT) 8-fold increase in intracellular accumulation HCPT solubility increased from 1.8 μg/mL (water) to 71.5 μg/mL (GA solution) AUC0-t: GL-HCPT Micelles (15.32 ± 1.21 h·μg/mL) was significantly higher than HCPT Injection (9.87 ± 0.95 h·μg/mL) ( Cai et al., 2019 ) Palmitoyl Pentapeptide-4 (PAL-4) PAL-4 solubility increased from 1 mg/mL to 20 mg/mL No clear PK data, but subcutaneous retention significantly increased Cumulative Permeation Amount increased 5.64-fold (10% GAO-SM Group) ( Wang et al., 2025b ) Licochalcone A (LicA) Skin deposition increased 12.86-fold LicA solubility significantly increased (specific fold not quantified) Cellular Uptake Rate increased to 96.52% (HaCaT cells) and 98.17% (melanocytes) ( Wang et al., 2022a ) Open in a new tab In the context of tumor therapy, copper ions serve a dual role; they function as essential crosslinking nodes within the gel network and generate reactive oxygen species (ROS) via Fenton-like reactions, thereby exerting direct chemokinetic cytotoxicity against tumor cells. Concurrently, the released GA provides inherent anti-inflammatory effects, working synergistically to reshape the immunosuppressive tumor microenvironment ( Pi et al., 2023 ). Moreover, this system demonstrates potent immunomodulatory capabilities, promoting the infiltration and activation of cytotoxic T cells at tumor sites ( Xu et al., 2023 ). Li et al. ( Li et al., 2025a ) demonstrated a composite system of GA with copper ions and protocatechuic acid driven by π-π stacking and metal coordination. This hydrogel exhibits excellent mechanical properties and sustained drug release characteristics in the treatment of diabetic wounds. Ge et al. ( Ge et al., 2023 ) demonstrated that the composite hydrogel SAGA (glycyrrhetinic acid-sodium alginate) captures endogenous Zn 2+ ions in prostate tissue via Zn 2 -mediated in situ gelation. This Zn 2+ capture mechanism not only regulates Zn 2+ levels in the prostate microenvironment but also alleviates local inflammation and inhibits glycolysis by converting free Zn 2+ into a bound state. T Yu et al. ( Yu et al., 2025 ) found that GA and rhein (Rh) could co-assemble into a supramolecular hydrogel system with hierarchical nanofiber structures. This GA-Zn-Rh hydrogel enhances the mechanical rigidity and toughness of the gel network through metal ion coordination, simultaneously improving antibacterial and anti-inflammatory effects. Beyond GA-based metal-coordinated systems, the structurally related polysaccharide counterpart, Glycyrrhiza polysaccharide (GP), can also be photo-crosslinked to form hydrogels with tunable mechanical strength, wherein the softer hydrogels were found to be more effective in promoting wound regeneration by reducing inflammation and fibrosis in an infected full-thickness skin wound model ( Wang et al., 2026 ). 4. The major functions of GA in transdermal drug delivery GA can form diverse nanoscale delivery systems, such as micelles, ionic liquids, and hydrogels. It exhibits four major functions in transdermal delivery: solubilization enhancement, stability improvement, permeation promotion, and skin targeting. 4.1. Enhancing drug solubility GA could remarkably improve the solubility of hydrophobic drugs. Its solubilization enhancement mechanisms primarily depend on molecular encapsulation and micelle formation ( Yang et al., 2024 ). Hydrophobic drug molecules are enclosed within a hydrophobic core formed by the steroidal backbone of GA, preventing direct contact with water molecules. Simultaneously, the external hydrophilic carboxyl groups ensure long-term stable dispersion of the entire assembly in the aqueous phase through hydration. This “core encapsulation-shell stabilization” architecture provides an ideal solution for transdermal delivery of poorly soluble drugs ( Ni et al., 2022 ). Based on the mechanism, GA displays exceptional solubilization capabilities in transdermal drug delivery. For instance, the THY@glycy micelles system achieved a remarkable encapsulation efficiency of 97.38% for the poorly water-soluble thymol ( Bailly and Vergoten, 2020 ), resulting in a fundamental transformation from a suspension to a transparent nano-coloidal solution. The GA-oxymatrine ion liquid self-assembled micelles (GAO-SM) increased the solubility of the hydrophobic signal peptide PAL-4 by approximately 20-fold ( Wang et al., 2018 ). Liang et al. enhanced drug retention in the dermis by 6.61-fold using GA-coptisine micelles (GA-CTS) ( Hou et al., 2022 ), significantly boosting topical drug delivery efficiency. In oral drug delivery, GA also demonstrates outstanding performance. For instance, Liu et al. reported that GA-paclitaxel nanoparticles (PGNs) boosted drug solubility by nearly 400-fold, achieving a drug loading capacity of 31.2% ( García-Salazar et al., 2023 ). Similarly, Cai et al. found that GL-HCPT injectable micelles not only raised hydroxycamptothecin solubility from 1.8 μg/mL to 71.5 μg/mL ( Yamashita et al., 2017 ), but also preserved its active lactone structure at physiological pH. Additionally, GA -berberine complex increased drug solubility by over 100-fold and improved oral bioavailability by 4.43-fold ( Afnan et al., 2012 ). In another study, Zhao et al. ( Ni et al., 2022 ) demonstrated that GA significantly enhances the solubility of anthraquinones such as emodin and aloe-emodin, elevating them from below detection limits to levels amenable to precise quantification. Furthermore, GA-baicalin nanomicelles increased baicalin's water solubility by over 4600-fold ( Rahman and Sultana, 2008 ), greatly enhancing its potential for applications in pharmaceutical formulations. In summary, GA could improve the solubility of various poorly soluble drugs, laying a solid foundation for their further application in transdermal or other delivery systems. 4.2. Enhancing drug stability GA also plays a crucial role in maintaining drug stability. Its stabilization mechanisms primarily stem from the physical encapsulation of drugs by the nanostructures. Additionally, the abundant functional groups within its molecular structure form hydrogen bonds and hydrophobic interactions with drug molecules. These interactions create a relatively isolated and ordered microenvironment that effectively shields drug molecules from adverse external conditions, such as pH fluctuations, enzymatic degradation, and oxidation. GA improves the stability of multiple active components in traditional Chinese medicine within simulated gastrointestinal environments. Zhao et al. systematically evaluated the impact of GA on the stability of 16 active traditional Chinese medicine components across simulated segments of the human digestive tract. The results revealed that the addition of GA significantly reduced the degradation rate constants of these components and extended their half-lives. Particularly, GA demonstrated the most pronounced stabilizing effect on flavonoid components such as quercetin and rutin in simulated gastric fluid environments, increasing their half-lives by 200% to 683% ( Ni et al., 2022 ). This protective effect persisted across varying pH conditions, highlighting the potent capacity of GA as a delivery carrier to maintain drug stability within complex physiological environments. Further mechanistic studies indicate that the enhancement of drug stability is closely associated with the specific microstructures formed by GA. Liu et al. investigated its stabilizing effect on INA by constructing two confined microdomain systems: GA micelles and GA gels ( Xu et al., 2020 ). They discovered that drug molecules are encapsulated within the nanofiber networks or micelle cores. This spatial confinement not only alters the drug's nucleation pathways and crystal selection but also effectively restricts the free movement of drug molecules, reducing their exposure to environmental degradation factors. For instance, the preferred crystal form of isoniazid remained stable for up to 20 months within the GA gel system, a marked extension compared to its mere 3 day stability in conventional solid state. This demonstrates that the GA system enhances both the chemical stability of the drug in solution and its stability in solid form, which is crucial for ensuring consistent and reproducible therapeutic efficacy. Additionally, encapsulating drugs within GA systems significantly improves their thermal stability. Taking curcumin as an example, free Cur exhibited a markedly reduced retention rate after 72 h at 60°C. However, when encapsulated in GA@Cur micelle hydrogels under identical conditions, Cur retention exceeded 83%, representing approximately a 1.6-fold improvement ( Chen et al., 2023 ). This indicates that the GA nanostructures provide an effective protective barrier for heat-sensitive drug molecules, limiting their thermal motion and shielding them from the effects of external high-temperature environments. In summary, GA enhances the chemical and physical stability of loaded drugs through physical isolation, restriction of molecular motion, and the formation of stable solid states. 4.3. Permeation-enhancing effects of GA As a natural saponin, GA exhibits significant permeation-enhancing capabilities in drug delivery systems. Its mechanisms primarily involve direct modification of biological membrane structures, regulation of transport proteins, and improvement of drug physicochemical properties. GA directly interacts with biological membranes, substantially increasing membrane permeability. Studies have demonstrated that GA enhances cell membrane permeability by approximately 60% while reducing membrane elastic modulus ( Dargel et al., 2021 ; Selyutina and Polyakov, 2019b ). This ability to alter membrane physical properties forms the crucial basis for its permeation-enhancing effect. In erythrocyte experiments, GA doubled the rate of formate ion permeation through membranes. Molecular dynamics simulations further revealed that GA molecules could embed into the “outer leaflet” of the lipid bilayer and carry water molecules into the membrane interior during penetration, thereby facilitating the transmembrane transport of small-molecule drugs. In studies involving the antiparasitic drug praziquantel, GA embedded in the lipid membrane forms hydrogen bonds with drug molecules diffusing toward the membrane center. This reduces the free energy barrier in hydrophobic regions, thereby enhancing transmembrane transport ( Kim et al., 2019 ) ( Fig. 6 ). Fig. 6. Open in a new tab Mechanisms of glycyrrhizin-assisted praziquantel transport across a lipid bilayer [119]. (a) Initial simulation setup for the lipid bilayer incorporated with four GA molecules (the surrounding water solvent is omitted for clarity). (b) Schematic of the simulated system: A DOPC lipid bilayer containing GA and PZQ molecules, solvated in water. Lipids are depicted as thin blue lines, water molecules in red, and the GA and PZQ compounds with thick line structures. (c、d、e) This figure illustrates several different scenarios of how the drug PZQ (represented by the red circle) penetrates a membrane. In case (a), PZQ penetrates the membrane without the presence of GA. Case (b) shows the process when there is one GA molecule involved. Case (c) depicts the situation with two GA molecules participating, and finally, (d) shows the penetration when PZQ interacts with a GA micelle. The whole penetration process is divided into six stages: first, the association between PZQ and GA occurs; then, PZQ adsorbs onto the membrane surface; next, it penetrates the membrane; after that, it diffuses into the subsequent half - layer of the membrane; subsequently, it exits from the membrane to the surface; and finally, it desorbs from the lipid bilayer. Reproduced with permission from A. V. Kim, E. A. Shelepova, O. Y. Selyutina et al., "Glycyrrhizin-Assisted Transport of Praziquantel Anthelmintic Drug through the Lipid Membrane: An Experiment and MD Simulation," Mol. Pharm., 2019, 16, 7, 3188–3198, DOI: 10.1021/acs.molpharmaceut.9b00317. Copyright 2019, American Chemical Society. When GA combines with oxymatrine (OMT) to form ionic liquid self-assembled nanomicelles (GAO-SM), it synergistically enhances the transdermal efficiency of poorly soluble peptide drugs. This system significantly increased the solubility of the model drug palmitoyl pentapeptide-4 (PAL-4) from 1 mg/mL to 20 mg/mL. Following treatment of 10% GAO-SM, the 24-h cumulative transdermal amount increased by 5.64-fold, with a notable rise in subcutaneous retention ( Wang et al., 2025b ). Furthermore, GA micelles substantially increased LicA penetration into skin, with skin deposition levels 12.86 times higher than those of free LicA. Laser confocal microscopy revealed that GA-LicA micelles primarily penetrated across the SC via the follicular pathway. Significant LicA fluorescence signals were detectable in the epidermis and follicles within 6 h, spread to the entire epidermis after 12 h, and into the dermis after 24 h ( Wang et al., 2022a ). Additionally, GA enhances drug retention and absorption by inhibiting efflux transporters on intestinal or cell membranes, such as P-glycoprotein (P-gp). In the oral delivery systems for paclitaxel, GA micelles not only effectively encapsulated the drug but also suppressed the activity of intestinal CYP3A enzymes and P-gp, significantly increasing paclitaxel absorption in the jejunum and colon regions ( Yang et al., 2015 ). Consistent with these experiments, further experiments confirmed that GA promotes the absorption of aconitine in the distal intestine, where P-gp is highly expressed ( Selyutina and Polyakov, 2019b ), indicating its pronounced inhibitory effect on P-gp. GA could also synergize with other pro-permeation agents to temporarily open tight junctions between epithelial cells, facilitating the paracellular transport of hydrophilic drugs. For instance, co-administration with sodium caprate reduces transmembrane resistance in Caco-2 cells, enhancing colonic absorption of the macromolecular drug calcitonin. In transdermal studies, GA combined with chitosan triples carvedilol permeability by modulating the epidermal barrier state. Especially, GA forms microporous channels in the epidermis and disrupts lipid bilayer structure, potentially representing an alternative mechanism for enhancing transdermal drug delivery [108]. Furthermore, GA-formed mixed micelles with Pluronic F127/TPGS significantly boost the oral absorption and hepatic accumulation of the payload, demonstrating a carrier self-enhancement effect ( Shen et al., 2020 ). For skin permeation, GA micelles enhance podophyllotoxin distribution within the epidermis while mitigating cutaneous inflammatory responses ( Kamath et al., 2024 ). 4.4. Targeted delivery of GA GA not only possesses permeation-enhancing properties but also serves as a highly promising natural targeted carrier. Its targeting mechanisms encompass passive targeting based on the enhanced permeability and retention (EPR) effect, active targeting mediated by receptor-ligand recognition, and natural targeting guided by hepatic metabolism. Self-assembled GA nanomicelles can exploit the EPR effect of solid tumor tissues to achieve passive accumulation at the target sites ( Su et al., 2017 ; Wang et al., 2025a ). Nanoparticles with diameters between 20 and 200 nm are able not only to effectively utilize the EPR effect but also evade rapid clearance by the reticuloendothelial system, enabling drug accumulation in tissues with enhanced vascular permeability, such as tumors and inflamed areas. For active targeting, GA achieves specific drug delivery by binding to certain cell surface receptors ( Choi et al., 2021 ). Hepatocytes express abundant GA receptors that specifically recognize and bind GA, conferring superior targeting properties to GA-modified drug carriers in liver cancer therapy ( Tian et al., 2014 ). Since this receptor is overexpressed on liver cancer cell surfaces, GA carriers minimize non-specific interactions with normal tissues, enhancing antitumor efficacy ( Hu et al., 2024 ). Furthermore, GA itself undergoes primary metabolism in the liver, conferring a natural hepatic targeting bias to carriers incorporating it ( Liu et al., 2023 ). Studies demonstrate that GA-modified nanocarriers accumulate more readily within hepatocytes due to their specific binding to hepatic membrane receptors, presenting a significant opportunity for targeted liver cancer therapy. Beyond liver-specific targeting, the use of GA can be extended to other diseased tissues ( Su et al., 2017 ; Wang et al., 2025a ). Simultaneously, inflamed tissues, characterized by increased vascular permeability, also serve as suitable targets for GA-based carriers. These multi-organ targeting properties position GA as a versatile targeted delivery vehicle with broad prospects in drug delivery systems. The targeted application of GA has further extended to skin and hair follicles. For hair follicle targeting, GA-based nanoscale systems can specifically accumulate within hair follicles, thereby achieving precise localization. For instance, Pluronic® F127-based polymeric micelles were developed to deliver benzoyl peroxide for acne treatment. Confocal laser scanning microscopy analysis confirmed that these nanomicelles specifically accumulate within hair follicles, achieving precise localization ( Kahraman et al., 2016 ). Mechanistic studies on the GA-LicA complex further revealed that hair follicles serve as a preferential pathway for drug penetration, and function as a “drug reservoir,” enabling local drug accumulation and sustained release. This provides a theoretical basis for treating follicle-related diseases ( Wang et al., 2022a ). For deeper therapeutic targets like cutaneous melanoma, pH-responsive cationic polymeric nanocarriers have demonstrated excellent skin penetration and tumor targeting capabilities, effectively delivering siRNA to lesion sites and inhibiting tumor progression ( Wang et al., 2020 ). In drug delivery research, ideal pharmacokinetic parameters are essential for topical or transdermal formulations. Paclitaxel, which is limited by poor oral bioavailability, was formulated into GA-based micelles by Yang et al. ( Yang et al., 2015 ) . GA-based micelles increased the oral AUC₀–₂₄ₕ from 0.57 μg·h/mL to 3.42 μg·h/mL—a sixfold improvement, while Cₘₐₓ rose 4.8-fold from 0.095 μg/mL to 0.460 μg/mL. These effects were attributed not only to enhanced solubility (from 0.67 to 124 μg/mL) but also to inhibition of intestinal P-glycoprotein, consequently improving drug absorption in the jejunum and colon. Similarly, Kamath et al.( Kamath et al., 2024 ) developed an ibrutinib-GA complex and GA-conjugated ovalbumen nanoparticles. Compared to free ibrutinib (Cₘₐₓ: 452.97 ng/mL; AUC₀–₄₈: 3,698.53 ng·h/mL), the complex increased Cₘₐₓ to 2168.21 ng/mL (4.8-fold) and AUC₀–₄₈ to 12722.75 ng·h/mL (3.44-fold). The nanoparticles also achieved 3.3-fold and 3.21-fold increases in Cₘₐₓ and AUC₀–₄₈, respectively. The complex also shortened Tₘₐₓ, suggesting faster absorption. Cai et al. ( Cai et al., 2019 ) examined intravenous hydroxycamptothecin-GA micelles. The accumulation in the liver was more than five-fold higher than the free drug, while distribution in the heart, spleen, lungs, and kidneys decreased. This liver-targeting effect enhances antitumor efficacy while reducing systemic toxicity. Finally, Kim et al. ( Kim et al., 2019 ) investigated praziquantel-GA complexes using an artificial membrane model. Cumulative permeation increased from 13.5 to 52 μg over 2.5 h, and permeability rose from 3.5×10 -4 to 9.0×10 -4 cm/min—a 2.6-fold enhancement. Complementary in vivo studies showed that GA enabled a tenfold reduction in therapeutic dose without loss of efficacy. Molecular dynamics simulations indicated that GA inserts into lipid bilayers and forms hydrogen bonds with praziquantel, reducing the energy barrier for passive diffusion. Together, these findings demonstrate that GA enhances drug bioavailability through multiple mechanisms: increasing oral absorption, enabling tissue-targeted delivery, and improving membrane permeability. 4.5. Synergistic self-assembly effects of GA with other saponins GA could also undergo synergistic self-assembly with other natural saponin molecules to form hybrid nanoaggregates with novel structures and enhanced properties. This hybrid system offers a new strategy for optimizing transdermal drug delivery performance. Studies have shown that mixing GA with tea saponins or aescin can modulate the morphology and interfacial properties of the self-assembled structures ( Baccile et al., 2021a ). Using techniques such as neutron scattering, Tucker et al. ( Tucker et al., 2021c ) discovered that when GA is mixed with other saponins, it forms mixed micelles or fibrous structures that are more stable than those of the individual components. This synergistic effect stems from the complementary nature of the intricate hydrogen-bond networks and hydrophobic interactions between different saponin molecules, enabling the mixed system to exhibit synergistic enhancement in lowering the critical micelle concentration, increasing drug loading capacity, and regulating drug release rates. Furthermore, these hybrid carriers constructed from all-natural saponins possess the inherent biological activities of their individual components, such as anti-inflammatory or antioxidant properties. They can promote transdermal drug absorption while exerting synergistic therapeutic effects, demonstrating potential as novel multifunctional transdermal delivery platforms ( Baccile et al., 2021a ). 5. Mechanism of GA in promoting skin permeability GA exhibits significant permeation-enhancing activity in transdermal delivery systems ( Selyutina and Polyakov, 2019a ). The SC is composed of keratin and lipid matrix, which restricts drug transport through skin due to its ordered “brick-and-mortar structure” ( Zeng et al., 2022 ). GA temporarily disrupts this barrier primarily through its interaction with SC lipids and with keratin ( Wei et al., 2018 ). These actions synergistically reduce diffusion resistance and enhance drug permeability. The reversibility and excellent safety profile make GA an ideal natural permeation enhancer ( Wang and Meng, 2017 ). ( Fig. 7 ) Fig. 7. Open in a new tab Illustration of the mechanisms enhancing drug stability, skin penetration, and retention via interactions with stratum corneum lipids and keratin. 5.1. Interaction with SC lipids SC lipids primarily consist of ceramides, cholesterol, and free fatty acids, forming a highly ordered lamellar bilayer that serves as the primary barrier against drug penetration ( Wang and Meng, 2017 ). First, GA disrupts this ordered structure by inserting into the lipid bilayer and extracting lipid components via increased lipid fluidity. The GA molecule comprises a hydrophilic glucose moiety and a hydrophobic glycyrrhetinic acid moiety, enabling it to embed within and bind to the hydrophobic regions of the lipid bilayer via hydrogen bonding and Van der Waals forces ( Selyutina and Polyakov, 2019a ). Molecular dynamics simulations reveal that GA penetrates the interior of the lipid bilayer, exhibiting particularly high affinity for cholesterol and ceramides ( Tan et al., 2025 ). This induces a transition in lipid molecular arrangement from an ordered “orthorhombic phase” to a more disordered “liquid crystal phase,” thereby reducing diffusion resistance ( Wang and Meng, 2017 ). In the DOPC lipid membrane model, the incorporation of GA induces measurable structural alterations that facilitate drug permeation. Molecular dynamics simulations reveal that a single GA molecule increases membrane thickness by approximately 0.2 nm and reduces the average area per lipid by about 0.05 nm 2 , reflecting tighter packing within the headgroup region ( Kim et al., 2019 ). More importantly, potential of mean force (PMF) calculations demonstrate that GA significantly lowers the midplane energy barrier from approximately 2.4 kT to 1.5 kT, a reduction of nearly 38%, while simultaneously deepening the potential well in the opposing leaflet by 2.0±0.3 kT ( Kim et al., 2019 ). These quantitative changes in the energy landscape promote the penetration of drug molecules such as praziquantel and nifedipine. This permeation-enhancing effect is similar to that of chemical permeation enhancers like nitroxole ( Kim et al., 2021 ; Kim et al., 2019 ). Furthermore, the self-assembly properties of GA help transport drug molecules to the lipid interface. By competitively binding lipid sites, it reduces drug-lipid interactions, thereby lowering the permeation energy barrier. Given its natural origin, GA offers higher safety and reversibility; the lipid barrier rapidly self-repairs upon discontinuation ( Selyutina and Polyakov, 2019a ). Furthermore, GA could weaken the barrier function by extracting SC lipids and disrupting their ordered structure. Sapra et al. demonstrated that GA treatment significantly reduces cholesterol and sphingosine levels in the SC, with reductions of 35.4% and 28.1%, respectively, compared to untreated controls, proving its capability to compromise the integrity of the lipid matrix through dissolution and extraction ( Kim et al., 2019 ). This effect was concentration-dependent; at a GA concentration of 1% (w/v), cholesterol content decreased from 78.3±2.1 μg/mg of skin to 50.6±1.8 μg/mg, while sphingosine levels declined from 45.2±1.5 μg/mg to 32.5±1.2 μg/mg ( Sapra et al., 2008 ). This biochemical alteration directly disrupts structural and physical properties. Differential scanning calorimetry (DSC) analysis revealed shifts in lipid and protein characteristic peaks alongside reduced enthalpy values in GA-treated epidermis. Concurrently, SEM and TEM observations revealed keratinocyte detachment, enlarged intercellular spaces, and disrupted lipid structures ( Kim et al., 2019 ). This cascade of changes, ranging from compositions to structures, creates more favorable penetration pathways for drug molecules. For instance, the combination of GA and chitosan exhibited the highest permeability enhancement ratio for carvedilol. Meanwhile, biochemical analysis revealed the greatest lipid extraction yield, attributed to GA's surfactant properties and its low mixing energy with lipids ( Sapra et al., 2008 ). Collectively, GA could temporarily and reversibly modulate skin barrier function through supramolecular interactions with SC lipids, thereby constituting a safe and effective transdermal delivery strategy. 5.2. Interaction with keratin GA could also interact with keratin in the SC, significantly enhancing transdermal drug penetration ( Zhu et al., 2020 ). The conformation and arrangement of keratin directly influence skin barrier function. Studies suggest that GA alters the secondary structure of keratin by interacting with specific residues, thereby temporarily reducing the barrier resistance of the SC ( Guo et al., 2025b ). In the ionic liquid formed by GA and oxymatrine, molecular docking reveals that the N + –O - domain of oxymatrine forms hydrogen bonds with keratin residues such as LEU, GLU, PRO, and TYR, with binding distances ranging from 2.4 to 3.2 Å, while GA and PAL-4 alone fail to dock effectively ( Wang et al., 2025b ). This interaction induces conformational changes in keratin, representing one of the key mechanisms enhancing SC permeability ( Rahman and Sultana, 2008 ). Further evidence from FTIR and DSC analyses shows that GAO treatment induces a blue shift in the amide I peak from approximately 1650 cm -1 to 1658 cm -1 and shifts the keratin denaturation peak to higher temperatures, confirming structural alterations in keratin ( Wang et al., 2025b ). Molecular dynamics simulations have further revealed that GA-based ionic liquids induce a “pull effect” for drugs within the SC through molecular dynamics simulations. During this process, interactions between GA and both keratin and lipids collectively reduce diffusion resistance, enabling efficient transdermal delivery. Liu et al. employed GA with paclitaxel into nanoparticles, dramatically improving the drug's solubility and skin retention. The enhanced transdermal efficacy of paclitaxel correlates closely with loosening of the SC keratin ( Xu et al., 2020 ). Taken together, GA binds to keratin through noncovalent interactions such as hydrogen bonds, altering its conformation. This effect offers novel approaches for the transdermal application of poorly soluble drugs and large-molecule peptides. 5.3. Comparison with traditional permeation enhancers GA, a natural amphiphilic saponin, exhibits permeation-enhancing mechanisms distinct from traditional chemical enhancers (e.g., POCC, Transcutol® P) and capsaicin. Traditional enhancers primarily disrupt stratum corneum lipids or alter keratin structure to reduce skin barrier function ( Wang et al., 2022b ). The molecular basis of this disruption is evident in FTIR analysis ( Fig. 8 a and Fig. 8 b), where traditional enhancers such as Span 80 induce blueshifts in the Amide I and Amide II bands of keratin, confirming their interaction with SC proteins. For instance, Span 80 induces Amide I and Amide II blueshifts from 1647.97 to 1648.41 cm -1 and from 1538.07 to 1539.55 cm -1 , respectively, while POCC shifts Amide II to 1538.65 cm -1 ( Fig. 8 a). In contrast, GA-based ionic liquids induce a more substantial Amide I shift from approximately 1650 to 1658 cm -1 (Δ = 8 cm -1 ), significantly greater than the 0.44–0.77 cm -1 shifts observed with traditional enhancers ( Wang et al., 2025b ), indicating a more pronounced alteration in keratin secondary structure. CLSM imaging ( Fig. 8 c) further reveals that enhancers like CP 90 and POCC significantly increase the fluorescence intensity and penetration depth of whitening agents, with hair follicles identified as a predominant permeation route. Capsaicin achieves its effects by activating TRPV1 channels, thereby widening intercellular gaps ( Wang et al., 2023 ). By contrast, GA operates through a multifaceted, gentler mechanism: it inserts into the lipid bilayer, binding to cholesterol and ceramides to induce a transition from ordered to disordered lipid phases, thereby increasing fluidity and reducing diffusion resistance. Simultaneously, GA binds to keratin residues via hydrogen bonds, inducing conformational changes that further weaken the barrier. Fig. 8. Open in a new tab Mechanisms of enhancer-mediated skin delivery. (a,b) FT-IR spectra showing C=O band shifts in Amide I/II regions of LicA-enhancer-skin (a) and Gla-enhancer-skin (b) systems, indicating keratin conformational changes. (c) CLSM images of LicA and C6 distribution in porcine skin (scale bar = 100 μm). Red arrows: stratum corneum; white arrows: hair follicles.Adapted from "Quantitative Structure-Activity Relationship of Enhancers of Licochalcone A and Glabridin Release and Permeation Enhancement from Carbomer Hydrogel" by Wang et al., 2022a , Pharmaceutics, 14, 2, 262, under CC BY 4.0 License. Copyright 2022, The Authors. Unlike traditional enhancers whose efficacy depends on log P or polarizability, GA exhibits strong "carrier dependency." Its amphiphilic structure enables self-assembly into micelles or hydrogels that encapsulate hydrophobic drugs, dramatically enhancing solubility and stability while promoting penetration. For example, GA-licochalcone A micelles increased skin deposition by 12.86-fold via follicular pathways ( Wang et al., 2022b ). This "carrier-enhancer-active ingredient" design endows GA with multifunctional capabilities—solubilization, stabilization, and targeted delivery that are not achievable with conventional enhancers. Regarding safety, traditional enhancers like capsaicin may cause irreversible lipid damage at high doses ( Wang et al., 2023 ). GA, as a natural compound, offers excellent reversibility. The lipid barrier rapidly self-repairs after discontinuation, providing a wider safety window despite mild cytotoxicity at high concentrations. Thus, GA represents a unique multifunctional natural enhancer with integrated carrier and penetration-enhancing properties for transdermal applications. 6. Toxicity and safety considerations As a natural active ingredient, GA demonstrates good skin compatibility in transdermal drug delivery applications. Nevertheless, its potential systemic side effects still require careful evaluation. The core advantage of GA transdermal formulations lies in their skin-targeting properties, which significantly increase drug deposition in the local skin layers while reducing the amount entering the systemic circulation, thereby reducing the risk of systemic toxic side effects at the source. However, GA itself possesses mineralocorticoid-like activity. The literature indicates that its intestinal metabolites, such as 3β-monoglucuronido-18β-glycyrrhetinic acid, 3MGA, could dose-dependently inhibit renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), leading to cortisol accumulation and excessive activation of the mineralocorticoid axis, thereby triggering “pseudo-hyperaldosteronism.” Long-term or high-dose systemic exposure may consequently cause hormone-like side effects such as hypertension, sodium and water retention, and hypokalemia with metabolic alkalosis. The occurrence of toxicity is closely related to dosage and interindividual metabolic differences; moreover, due to the enterohepatic circulation, plasma clearance is relatively slow( Caré et al., 2023 ). Therefore, in the design of transdermal drug delivery systems, ensuring that GA remains primarily at the site of action on the skin and minimizing its systemic absorption is key to controlling these risks. Existing GA-based nanocarriers (such as micelles and nanofibers) have demonstrated potential in reducing systemic exposure in experiments by enhancing drug retention in the stratum corneum and targeting hair follicles. Future safety studies should focus on the transdermal absorption kinetics of GA in different transdermal formulations, as well as the assessment of local and systemic toxicity following long-term use, along with strategies to further reduce its mineralocorticoid activity through chemical modification or composite delivery systems. 7. Summary and Outlook GA demonstrates broad application prospects in drug delivery due to its unique amphiphilic structure. Driven by hydrophobic forces, hydrogen bonding, π–π stacking, and electrostatic interactions, GA molecules spontaneously assemble into diverse ordered nanostructures within aqueous phases, including dimers, micelles, nanoparticles, nanofibers, and even hydrogels. These self-assembled structures not only serve as drug carriers to enhance the solubility and stability of poorly soluble drugs, but also offer promising permeation enhancement, transdermal biocompatibility, and synergistic therapeutic potential in transdermal and other delivery routes. This review systematically elucidates the self-assembly behaviors and mechanisms of GA, the potential as a drug carrier, its functions in transdermal delivery, and the mechanisms of permeation enhancement. The self-assembly of GA is a highly environment-dependent dynamic process. GA self-assembly commences with dimer formation, which lays a crucial foundation for the subsequent construction of more complex nanostructures. The configuration of dimers has evolved from the early “L-shaped lateral stacking” to the revised “a more compact building block”, and most recently to the “tail-to-tail hydrophobic core-shell” model. The dimer configuration exhibits high sensitivity to factors such as pH, ionic strength, and temperature. Discrepancies in morphological parameters reported by different research groups stem partly from variations in characterization methods and partly from subtle differences in sample preparation conditions. Consequently, the growth mechanisms, precise molecular mechanisms driving specific conformational formation, and transformation pathways remain core challenges in current research. Integrating computational simulations with advanced characterization techniques under different conditions represents a new direction. In addition, the formation of its higher-order assembly structures, like micelles, nanofibers, and hydrogels, is strictly controlled by molecular concentration, environmental pH, and temperature. For instance, micelles predominantly form at weakly acidic pH values 4–6 with a rod-like morphology, while nanofibers remain stable within the pH range of 3–5 and exhibit right-handed helical characteristics. Hydrogel formation typically requires concentrations exceeding the critical gel concentration and is often triggered by a “heat-cool” cycle. GA displays multifaceted advantages as a drug carrier, including natural origin, excellent biosafety, and superior solubilization and stabilization capabilities( Kumari et al., 2025 ). GA could form diverse nanostructures such as micelles, nanofibers, nanoparticles, and hydrogels with poorly soluble and poorly permeable drugs, effectively enhancing their solubility, stability, and bioavailability ( Ni et al., 2022 ). In drug delivery applications, it encapsulates poorly soluble drugs within its hydrophobic core to dramatically increase their apparent solubility. Moreover, it protects drugs from degradation through core-shell structures or three-dimensional networks, enabling sustained release and targeted delivery. However, GA faces challenges in transdermal enhancement. First, when GA is used as a permeation enhancer alone, its enhancement efficiency remains limited compared to certain highly effective permeation enhancers. In particular, when loading highly hydrophobic drugs, their permeation-enhancing effect could not meet clinical demands ( Wang et al., 2016 ). Next, while GA-based hydrogel drug delivery systems exhibit good biocompatibility and injectability, their mechanical strength is generally low. They are prone to structural damage under in vivo or in vitro stress, leading to drug burst release or premature carrier degradation, making sustained-release difficult to achieve. Moreover, the stability of GA dimers and their higher-order assembly structures is susceptible to environmental factors, posing challenges for formulation quality control. Multiple optimization strategies could address these issues. To enhance permeation efficiency, a combined use of GA with other natural or synthetic permeation enhancers can be performed ( Shen et al., 2020 ). Concurrently, surface modifications or co-assembly with functional excipients can reduce the dosage of GA. To address the mechanical weakness of hydrogels, strategies such as dual-network crosslinking, nano-composite reinforcement, or dynamic covalent bonding could be employed. 8. Reliability and limitations This review searched for and analyzed recent literature on the self-assembly of GA and its transdermal applications up to 2025. The self-assembly conditions, mechanistic insights, and drug delivery data summarized here are all drawn directly from published experimental studies. However, these studies also have certain limitations. Although the literature coverage is relatively comprehensive, due to constraints in search strategies and databases, it may not have captured all relevant studies; furthermore, the included studies are predominantly preclinical experiments, lacking clinical data to support their findings. Additionally, discussions regarding certain self-assembly mechanisms remain based on inferences from existing literature, lacking a unified, quantitative theoretical model for integration. Furthermore, differences in the experimental models, conditions, and methods used by various research teams to evaluate the performance of GA drug delivery systems make it difficult to conduct direct, quantitative cross-comparisons of some data. Finally, while the review focuses on elucidating scientific principles and application potential, the discussion regarding the specific challenges these GA-based nanosystems face in terms of large-scale production, formulation stability, long-term storage, and regulatory compliance is relatively limited. These limitations provide clear directions for future systematic experimental validation, standardized evaluation methods, and the advancement of translational research. CRediT authorship contribution statement Lin Zhou: Writing – original draft, Validation, Methodology, Investigation. Youran Deng: Writing – original draft, Methodology, Investigation. Mingjie Ou: Software, Investigation. Zhuxian Wang: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization. Consent for publication All authors agreed to submit this manuscript. 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