α-Helical peptides: design strategies and recent advances in biomedical applications.

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Learn more: PMC Disclaimer | PMC Copyright Notice J Transl Med . 2026 Apr 20;24:728. doi: 10.1186/s12967-026-08161-7 α-Helical peptides: design strategies and recent advances in biomedical applications Mengyuan Yin 1 , Fei Ding 1, 2 , Guanghua Luo 1, ✉ , Miaomei Yu 1, ✉ Author information Article notes Copyright and License information 1 Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003 China 2 Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001 China ✉ Corresponding author. Received 2026 Jan 27; Accepted 2026 Apr 12; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13231750  PMID: 42010675 Abstract Background The α-helix, a fundamental and highly versatile secondary structure in proteins, holds substantial promise in biomedicine owing to its characteristic right-handed helical conformation, regular hydrogen-bonding network, and predictable side-chain arrangement. Main body This review systematically outlines the structural features and stabilization mechanisms of α-helical peptides, along with core strategies in drug design, including solid-phase peptide synthesis (SPPS), ring-opening polymerization (ROP) of N -carboxyanhydrides (NCAs), conformational stapling, non-natural amino acid incorporation, and stimuli-responsive modifications. We also highlight frontier advances in computational simulation and deep-learning approaches for de novo structural prediction and functional optimization. Regarding applications, this review elaborates on the mechanisms and recent progress of α-helical peptides in antimicrobial and anticancer therapies, immunomodulation, and tissue engineering, covering membrane-targeting mechanisms, immune cell modulation, vaccine design, drug delivery systems, and bioactive regenerative scaffolds. Conclusions Despite their superior biocompatibility, functional programmability, and translational potential of α-helical peptides, challenges remain including in vivo stability, scalable manufacturing, and optimizing pharmacokinetics. Future advances driven by multidisciplinary integration and artificial intelligence (AI)-guided design are expected to further enable α-helical peptides as pivotal tools in precision and regenerative medicine. Keywords: α-Helical peptides, Antimicrobial peptides, Anticancer therapy, Immunomodulation, Drug delivery, Tissue engineering Introduction The α-helix, one of the most common and functionally versatile secondary structures in proteins, provides high stability and structural specificity, endowing α-helical peptides with notable advantages in biomedical applications [ 1 – 3 ]. Since its three-dimensional model proposed by Linus Pauling, Robert B. Corey, and H. R. Branson in 1951, the α-helix has been widely recognized as a core unit in protein folding and function, owing to its unique right-handed helical conformation and the polar distribution of amino acid side chains [ 4 ]. Subsequently, Jack D. Dunitz, through his work in chemical crystallography and conformational analysis, emphasized the general importance of helical structures in molecular architecture, further highlighting their essential role in biological macromolecules [ 5 ]. Notably, α-helices can be categorized into distinct types based on the physicochemical properties of their constituent amino acids, differing primarily in their polarity and hydrophobicity distributions, which directly affect their biological functions and intermolecular interactions [ 6 ]. Compared with random coils, the α-helix endows peptides with increased rigidity, an ordered and predictable conformation, and enhanced membrane penetration, structural stability and target-interaction capacity at the biological interfaces [ 7 ]. These properties substantially improved the suitability of peptides for drug delivery, gene transfection, and immunomodulation [ 8 ]. Recent advances in peptide synthesis and structural biology have spurred the development of engineered α-helical peptides, showing considerable promise in antibacterial, anticancer, and immunotherapeutic applications [ 9 , 10 ]. For example, a 12-residue α-helical fragment derived from the Enterococcus EntV peptide exhibited potent antifungal activity against Candida albicans . Activity was further augmented through synthetic optimization, and the peptide demonstrated efficacy in animal models, suggesting a potential new therapeutic strategy against drug-resistant fungal infections [ 11 ]. Similarly, α-helix-based multiepitope vaccines could elicit specific immune responses against multidrug-resistant Serratia marcescens , demonstrating potential for preventing infection [ 12 ]. At the molecular level, the stability of α-helices is critical for their function. Studies have shown that the type and concentration of metal ions can modulate protein conformation, including that of intrinsically disordered proteins, influencing the formation and stability of α-helical structures [ 13 ]. This mechanism is particularly relevant to neurodegenerative diseases. For example, dysregulation of metal homeostasis (e.g., Zn²⁺, Cu²⁺) drove pathological conversion of Aβ and α-synuclein from native soluble states which might contain helical structures to β-sheet rich pathogenic aggregates [ 14 ]. Moreover, chemical modifications such as amino acid substitution and stapling can effectively enhance helical stability, protein binding affinity, and cell membrane permeability, laying the foundation for developing intracellular-acting peptide drugs [ 15 ]. Furthermore, α-helices play a critical role in membrane protein folding and insertion, where the lipid environment modulates the free-energy landscape to influence proper folding and function, offering insights for designing membrane-associated α-helical peptides [ 16 ]. The side-chain arrangement of α-helices also offers a spatial template for the precise presentation of functional motifs, facilitating stimulus responsiveness, targeted recognition, and bioactivity modulation [ 17 ]. Collectively, α-helical peptides, with their stable secondary structure and high functional plasticity, have emerged as promising therapeutic agents for anti-infective, antitumor, and immunomodulatory applications when integrated with modern synthetic and computational biology technologies. This review summarizes the current application progress and mechanistic paradigms which will facilitate clinical translation and guide future molecular design and optimization (Fig. 1 ). Fig. 1. Open in a new tab Schematic illustration showing the designs and applications of α-helical peptides in biomedicine. AMPs: antimicrobial α-helical peptides; NCAs: N -carboxyanhydrides; ROP: ring-opening polymerization; SPPS: solid-phase peptide synthesis Structural features and design strategies of α-helical peptides Molecular structure and stabilizing factors of α-helical peptides The α-helix is a regular secondary structure stabilized by an extensive hydrogen-bonding network, in which a carbonyl oxygen atom of the backbone forms a hydrogen bond with the amide hydrogen atom located four residues downstream (i → i + 4). This pattern generates a stable, right-handed helical framework. For example, in the ion channel-like pore structure formed by Aβ (1–40) peptides, Cα-H···O non-classical hydrogen bonds within GXXXG motifs can augment inter-helical connectivity, reinforcing the pore structural stability [ 18 ]. Although the stabilizing contribution of such interactions may remain controversial, numerous molecular dynamics (MD) and quantum mechanical calculation studies have confirmed their role in stabilizing peptide and protein structures [ 19 – 21 ]. The arrangement of side chains is another key factor influencing helix stability. Hydrophobic residues tend to coalesce, forming a hydrophobic core that reduces the interfacial energy between the helix and aqueous phase, thereby promoting overall structural stability. For instance, the C- and N-termini of α-helices are often rich in hydrophobic or polar residues, which facilitates the spatial positioning and folding stability of the helix [ 22 ]. Polar residues also participate in helical structural stabilization through the formation of salt bridges and hydrogen bonds. Studies have shown that the stability of α-helices in certain transmembrane proteins depends on interactions between their polar residues and the membrane environment [ 23 ]. Furthermore, α-helices exhibit dynamic properties within the overall protein structure. For example, in the lotus root polyphenol oxidase (PPO), the extension and rupture of α-helices are closely correlated with enzyme activity, and specific helical regions can stabilize the substrate binding site to facilitate the catalytic process [ 24 ], which indicates that the stability of α-helices depends not only on local hydrogen bonds and side-chain interactions, but also on their functional state. Specific sequences such as the GXXXG motif regulate the assembly mode of peptides or proteins by promoting specific inter-helical interactions, thereby influencing their structure and function [ 18 ]. The distribution of hydrophobic and polar residues, in turn, determines the positioning and stability of helices in a membrane environment, affecting the overall conformation and dynamics of the protein [ 23 ]. Collectively, the stability of α-helices arises from the regular arrangement of backbone hydrogen bond networks and side-chain-mediated modulation through hydrophobic interactions, polar interactions, and specific structural motifs such as the GXXXG sequence. The integration of MD simulations with experimental biophysical methodologies provides powerful tools for elucidating these stabilization mechanisms, thereby offering critical guidance for the rational design of highly stable peptide therapeutics and functional proteins [ 18 , 23 , 24 ]. Synthesis and modification strategies of peptides Peptide synthesis and modification are fundamental for preparing stable α-helical peptides. The primary methods include solid-phase peptide synthesis (SPPS) and N -carboxyanhydride (NCA)-based ring-opening polymerization (ROP). SPPS is widely used for the synthesis of α-helical peptides due to its high efficiency, automation, and ease of purification [ 25 ], allowing peptide chain elongation via stepwise coupling of amino acids to a solid support resin (Fig. 2 a). Recent advances include the introduction of non-natural amino acids and specialized structural motifs such as quaternary α-arylated amino acids (Q4As), which can modulate peptide folding behavior and stability, promoting α-helix formation and maintenance [ 26 ]. ROP of NCAs offers unique advantages for the rapid synthesis of high-molecular-weight poly(α-amino acids), typically initiated by nucleophiles (e.g., primary amines) or bases (e.g., tertiary amines and alkoxides) (Fig. 2 b) [ 27 – 29 ]. Moreover, various novel catalytic systems such as transition metal catalysts and organosilicon amine compounds have been developed to enable precise control over molecular weight and stereoregularity [ 30 , 31 ]. Fig. 2. Open in a new tab Design strategies of α-helical peptides. ( a ) General SPPS methodology for peptide synthesis via deprotection, amino acid activation, and coupling [ 25 ]. Copyright 2021, American Chemical Society. ( b ) Spherical unimolecular micelles formed through surface NCA polymerization [ 29 ]. Copyright 2020, American Chemical Society. ( c ) Construction of enzyme-responsive polypeptides with adjustable conformations for diagnostic imaging and photodynamic therapy [ 46 ]. Copyright 2023, American Chemical Society. ( d ) Interactions between PO5 and Bcl-xl residues observed during molecular simulation [ 48 ]. Copyright 2022, Elsevier. ( e ) Flowchart of the de novo design methodology for generating helical peptide structures coined as HelixGAN [ 50 ]. Copyright 2023, Oxford University Press. ALP: alkaline phosphatase; Cy5: Cyanine 5; Ce6: Chlorin e6; DP: degree of polymerization; GNP: gold nanoparticle; NCA: N -carboxyanhydride Cyclization modification is an effective approach for stabilizing α-helical peptide conformations. By introducing chemical crosslinkers at specific positions within the peptide chain, as in intramolecular cyclization or stapling, the conformational flexibility can be effectively reduced, thereby enhancing the thermodynamic stability and proteolytic resistance of the helix. For instance, hydrocarbon stapling via ring-closing metathesis (RCM) of olefinic side chains at the i and i + 4 positions creates a covalent bridge that significantly stabilizes the α-helical structure while allowing tuning of bridge length, stereochemistry, and orientation, which modulates stapling efficiency and helical stability [ 32 , 33 ]. Recent studies have also reported that multicomponent macrocyclization reactions can provide conformational constraint while enabling the incorporation of multifunctional side chains, thereby expanding design diversity [ 34 ]. The incorporation of non-natural amino acids represents another important strategy for enhancing the functionality and stability of α-helical peptides. Non-natural amino acids such as α-amino acids, β-amino acids, and their derivatives can endow peptides with enhanced structural rigidity and proteolytic resistance. For instance, D/L-enantiomers of Q4A leveraged its unique spatial configuration to effectively modulate the α-helical propensity of peptide chains: certain stereoisomers enhance helical stability via optimal backbone dihedral angle (φ, ψ) geometries, whereas alternative configurations disrupt helical continuity [ 26 ]. β-Amino acid derivatives containing nitrogen heterocycles, such as cis-5-amino-azacyclohexane-4-carboxylic acid (cis-AAzC), promoted the formation of unconventional 11/9- or 12/10-helical structure through backbone conformational modification, thereby improving the water solubility and biocompatibility [ 35 ]. The incorporation of non-natural amino acids can also modulate the amphipathicity and functional properties of peptides by adjusting the hydrophobicity, charge, and steric hindrance of amino acid side chains, thereby influencing their cell permeability and targeting capabilities [ 36 , 37 ]. The off-target effects of helix-stabilized peptides primarily stem from their amphipathic structure-induced membrane interactions and hydrophobicity-mediated non-specific protein binding. These risks can be significantly mitigated through rational sequence design, charge optimization, and staple engineering, enabling the development of therapeutic peptides with high target indices. Stereochemical modification also plays a crucial role in modulating peptide function. For example, macrocyclic N-capping motifs containing D-amino acids can enhance α-helical stability. This facile and versatile modification is well-suited for peptide library screening and inhibitor development [ 38 ]. D-peptides, as the enantiomeric counterparts of natural L-peptides, have attracted much attention in peptide drug design owing to their proteolytic resistance and superior pharmacokinetic properties. Mirror-image phage display combined with computer-aided drug design platforms (e.g., finDr) enables efficient screening of target-specific D-peptide ligands, supporting the development of antibody-mimetic therapeutics [ 39 ]. In addition to chemical modifications, stimuli-responsive modifications also endow α-helical peptides with dynamic responsiveness to changes in the external and internal environments, such as light, temperature, redox state, pH, and enzymatic activity [ 40 – 42 ]. For example, azobenzene-containing macrocyclic peptides can undergo reversible light-induced conformational switching, dynamically modulating their α-helical content and associated biological activity, which provides new avenues for developing light-controlled drugs and functional biomaterials [ 43 ]. Selenium-containing polypeptides incorporating selenoether (-Se-) side chains are responsive to reactive oxygen species (ROS). Upon exposure to extremely low concentrations (0.1%) of hydrogen peroxide (H₂O₂), oxidation to hydrophilic selenoxides triggers a conformational transition from random coil to α-helix. This can induce disassembly of self-assembled micelles and enable controlled release of encapsulated anticancer drugs such as doxorubicin (DOX) [ 44 ]. Nanoparticles (DNP) formed via electrostatic complexation of cationic oncolytic peptides (PLP) with pH-sensitive anionic peptides can undergo charge reversal in the acidic tumor microenvironment (pH 6.8), restoring membrane-lytic activity [ 45 ]. A protein-mimetic nano-switch composed of a gold nanoparticle (GNP) core, a synthetic peptide linker, and an optically functional molecule (OFM) can be activated by alkaline phosphatase (ALP) overexpressed by tumor cells. ALP-mediated dephosphorylation triggers a conformational transition of polypeptide from flexible random coil to rigid α-helix, which can be used to regulate fluorescence imaging or photodynamic therapy (Fig. 2 c) [ 46 ]. In conclusion, SPPS and ROP of NCAs provide an efficient platform for producing α-helical peptides, whose helical stability, functional diversity, and biomedical application potential are significantly expanded by cyclization, non-natural amino acid incorporation, and stimuli-responsive modifications. These techniques not only improve the conformational stability and bioactivity of peptides but also enhance cell penetration, proteolytic resistance, and pharmacokinetic properties, establishing a solid foundation for the development of peptide-based therapeutics and biomaterials [ 47 ]. Computational design and structure prediction Computational simulation and structure prediction play an increasingly crucial role in the design and optimization of α-helical peptides. Methods such as MD simulation, homology modeling, and deep learning can elucidate the three-dimensional structures, dynamic behaviors, and interactions with targets of peptides, providing a theoretical foundation and predictive insights for rational peptide drug design. As an atomistic-scale dynamics method, MD simulation can dynamically model the conformational changes and stability of peptides in solution or a membrane environment. For example, in the design of anticancer drugs for anti-apoptotic protein (Bcl-xl) inhibitors, the optimized pentapeptide sequence (PO5) was screened by molecular docking combined with Taguchi method. MD simulation then verified its stable binding to the Bcl-xl BH3 domain, showing a stronger affinity than existing compounds (Fig. 2 d) [ 48 ]. Homology modeling predicts three-dimensional structures of target peptide based on homologous proteins with known structures, providing starting conformations for subsequent molecular docking and MD simulations. For example, in a study on inhibiting the Wnt signaling pathway in colorectal cancer, a peptide was designed based on the homology model of secreted frizzled-related protein 1 (SFRP1). Molecular docking and MD simulations predicted that it could maintain a stable α-helical structure and effectively bind to the Wnt2 ligand, with subsequent experiments confirming its biological activity [ 49 ]. This demonstrates the guiding potential of computational methods in peptide structure prediction and functional design. Deep learning approaches, such as HelixGAN, enable de novo design of α-helical structures at the atomic level using generative adversarial networks, with gradient-based optimization of specific residue conformations. These generated structures show high consistency with those predicted by traditional tools like PEP-FOLD and exhibit superior performance in modeling receptor binding stability, representing the latest advances in computational peptide design (Fig. 2 e) [ 50 ]. Computational simulation methods offer significant advantages in optimizing peptide structure and function. First, they can elucidate the binding mode, energetic contributions, and dynamic stability of peptide-target interactions at the molecular level to guide sequence optimization. Second, virtual screening and iterative design cycles can reduce experimental costs and time while improving screening efficiency. Third, by integrating machine learning, these methods can identify potential bioactive peptides from large sequence datasets and design novel molecules with tailored functions. However, these calculation methods also have certain limitations. First, MD simulations are quite sensitive to force field and solvent model, and existing force fields have known limitations in modeling protein-protein/peptide interactions [ 51 ]. Second, high computational cost restricts the scale and timescales accessible for simulation. Third, simulation results require experimental validation, as predicted binding affinities or activities may deviate from reality. For example, some designed peptides fail to effectively block target binding in in vitro competitive binding assays. Fourth, while deep learning-generated structures show promise, their training relies on large, high-quality datasets, and often lacks the ability to directly predict kinetic or thermodynamic parameters. Computational simulation and structure prediction techniques provide powerful tools for designing α-helical peptides, accelerating the development and functional optimization of peptide drugs. Future improvements in force fields, computational resources, and data integration will expand their applicability. Nevertheless, experimental validation remains essential to enhance predictive accuracy and translational relevance. Synthesis, modification, and computational design strategies for α‑helical peptides are summarized in Table 1 . Table 1. Synthesis, modification, and computational design strategies for α‑helical peptides Category Specific strategy/technique Core principle and function Typical application/advantage References Core synthetic methods Solid-phase peptide synthesis (SPPS) Efficient, automated, sequence‑controlled synthesis of short peptides Customized preparation of functional α‑helical peptides [ 25 ] Ring-opening polymerization (ROP) of N -carboxyanhydrides (NCAs) Rapid preparation of high‑molecular‑weight, structurally regular poly(α‑amino acids) Scalable production of peptide‑based polymeric materials and carriers [ 27 – 31 ] Conformational stabilization modifications Hydrocarbon stapling (e.g., RCM) Covalent ring formation at i, i+4/7 positions; dramatically enhancing helical content and protease resistance Stabilized therapeutic peptides (e.g., SAH‑FOXP3), prolonged in vivo half‑life [ 32 , 33 ] Multicomponent macrocyclization Providing rigid conformational constraint while enabling the incorporation of multifunctional side chains Design of cyclic peptide libraries with complex functions [ 34 ] Functional modifications Incorporation of non-natural amino acids (Q4As, β-amino acids) Modifying backbone/side‑chain properties, enhancing rigidity, stability, or introducing new functions Q4As increase helicity; β‑amino acids form non‑canonical helices, improving water solubility [ 26 , 35 ] Stereochemical modification Enhancing proteolytic resistance, improving pharmacokinetic properties D‑peptide drug development, mirror‑image phage screening [ 39 , 52 ] Stimuli-responsive modifications (light, temperature, redox state, pH, enzymatic activity) Imparting environment‑triggered conformational transitions and functional responsiveness Smart drug delivery, controlled release, and theranostic integrated systems [ 43 – 46 ] Molecular dynamics (MD) simulations Atomic‑level simulation of conformational dynamics, binding modes, and stability Guiding sequence optimization, validating binding mechanisms (e.g., PO5 with Bcl-xL) [ 48 – 50 ] Homology modeling and molecular docking Predicting structures of unknown peptides and interactions with targets Designing active peptides based on known protein structures (e.g., SFRP1) [ 49 ] Deep learning (e.g., HelixGAN) De novo generation of α‑helical structures with desired properties Efficiently exploring novel peptide sequence space, accelerating lead discovery [ 50 ] Open in a new tab In summary, to ensure the correct structural integrity required for helical peptide function in complex biological environments, a systematic integration of methodologies across three distinct levels is essential. At the sequence design level, helical propensity can be enhanced through the strategic incorporation of α,α-disubstituted amino acids (e.g., Aib, Dpg) or N -methyl amino acids. Concurrently, computational algorithms should be employed to predict helical stability, coupled with optimization of hydrophilic and hydrophobic residue distributions to preserve critical amphipathic characteristics. At the chemical modification level, helical conformations can be covalently locked via hydrocarbon stapling, thioether bridging, or lactam cyclization, with the resulting helical content validated through circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Finally, at the quality control level, structure-activity relationship (SAR) studies should be established to correlate helicity with biological activity, while molecular dynamics simulations are employed to predict conformational behavior in solution. Additionally, structural stability should be assessed through protease susceptibility assays to ensure robustness under physiological conditions. Advances of α-helical peptides in biomedicine Antibacterial applications of α-helical peptides Elucidation of antimicrobial mechanisms α-Helical antimicrobial peptides (AMPs) exert potent antimicrobial activity through interaction with bacterial membranes, encompassing membrane disruption, penetration, and immune activation [ 53 ]. Their amphipathic structure, characterized by hydrophobic and positively charged hydrophilic side chains, enables selective recognition and binding to the negatively charged bacterial membranes. By interacting with anionic lipids such as phosphatidylglycerol (PG) and phosphatidylserine, AMPs can increase membrane permeability, induce pore formation or membrane disruption, leading to the leakage of intracellular contents and consequently bacterial death. For example, the antimicrobial peptide C6-10 rapidly forms a stable α-helical structure in bacterial membrane models, adsorbs firmly onto the membrane surface, and induces structural perturbations. It preferentially binds to negatively charged PG via electrostatic interactions, thereby disrupting the bacterial membrane (Fig. 3 a) [ 54 ]. In addition to direct membrane disruption, some α-helical peptides can also penetrate the cell membrane to target intracellular targets, such as nucleic acids or metabolic enzymes, which enhances their bactericidal effect [ 53 ]. For example, studies have shown that some AMPs derived from glyceraldehyde-3-phosphate dehydrogenase (GAPDH) exhibit a mixed mode of pore formation and intracellular action [ 55 ]. The antimicrobial activity of peptides is primarily co-regulated by their positive charge density and hydrophobicity. Cationic residues mediate the initial electrostatic attraction to negatively charged bacterial membranes, while hydrophobicity facilitates the subsequent insertion of the peptide into the lipid bilayer, promoting membrane disruption [ 56 , 57 ]. Fig. 3. Open in a new tab Antimicrobial applications of α-helical peptides. ( a ) Schematic diagram of a helix-transformable antimicrobial polypeptide (C6-10) with enhanced antibacterial selectivity [ 54 ]. Copyright 2025, American Chemical Society. ( b ) Schematic illustration of PPa-cP preparation for combating fungal biofilms [ 64 ]. Copyright 2022, John Wiley & Sons. C. albicans: Candida albicans; CLG-NCA: γ-(6-Chlorohexyl)-l-glutamate- N -carboxylanhydride; cP: cationic polypeptide; HT-AMP: helix-transformable antimicrobial polypeptide; NIR: near-infrared radiation; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PG: phosphatidylglycerol; PPa: pyropheophorbide a; ROS: reactive oxygen species Immune activation constitutes another important antimicrobial mechanism. Some α-helical peptides can modulate host immune responses, such as activating macrophages and other immune cells, thereby enhancing the host defense against pathogens. This has been demonstrated in vitro with peptides that activate macrophage cell lines like RAW 264.7 [ 58 ]. Additionally, α-helical peptides also exhibit inhibitory and disruptive effects against bacterial biofilms, thereby reducing the risks of drug resistance and persistent infection. The designed D-amino acid-containing α-helical peptides effectively inhibited biofilm formation, as confirmed using a real‑time observation model (CoMIC) [ 52 ]. In summary, α-helical AMPs achieve efficient binding to bacterial membranes through their amphipathic structure, leading to membrane disruption and penetration while also potentially activating host immune defense. Their anti-biofilm activity further enhances the antibacterial effect. By optimizing the helical structure, positive charge distribution, and hydrophobicity, their antibacterial activity and selectivity can be improved, advancing their applications in biomedicine [ 59 , 60 ]. Preclinical and clinical applications α‑helical peptides demonstrate considerable potential for clinical applications in antibacterial and antifungal fields. Taking inspiration from cell‑penetrating peptides, guanidinium‑functionalized peptide‑mimetic polymer nanoparticles (TPE‑Parg) have been designed. These nanoparticles combine blue-light imaging capability with intracellular bactericidal function, and their antibacterial activity is modulated by cationic groups and chain length [ 61 ]. Another strategy involves fusing structural domains from highly active AMPs. For instance, a hybrid peptide named LM1, designed by combining elements of Melittin and Lasioglossin (LL-III), maintained a stable α-helical conformation. MD and coarse-grained simulations indicated strong interactions with bacterial membranes, correlating with significantly enhanced antimicrobial activity against Staphylococcus aureus and Acinetobacter baumannii [ 62 ]. Such domain-fusion approaches can enhance targeting while preserving structural stability, offering new avenues for antimicrobial drug design. In the antifungal field, the EntV peptide derived from Enterococci inhibited Candida albicans and its drug-resistant strains via its 12-amino-acid α-helical core fragment. It showed significant protective effects in mouse models of oropharyngeal and systemic candidiasis. Subsequent optimization through systematic mutational screening and chemical modification further improved its antifungal activity and stability, underscoring the value of α-helical peptides in the development of novel antifungal drugs [ 63 ]. A photosensitizer-polypeptide conjugate (PPa-cP) enhanced binding to the surface of Candida albicans via electrostatic interactions. This conjugate not only exhibited potent antifungal activity in vitro but also penetrated biofilms efficiently, enabling effective clearance through photodynamic therapy (Fig. 3 b) [ 64 ]. Against bacterial biofilms, several innovative designs have shown promise. The brush polymer Dex-G15E15, featuring a dextran backbone and mixed-charge polypeptide side chains, effectively penetrated and disrupted biofilms on endotracheal tube surfaces, significantly reducing lung infection and inflammation in mouse models [ 65 ]. A cyclic cationic poly(α-amino acid) (cPCHLG10-C8) was designed to reduce cytotoxicity by diminishing the degree of α-helix conformation while maintaining potent membrane-killing activity against Staphylococcus aureus . It efficiently cleared biofilms in infected wound models with negligible propensity to induce bacterial resistance [ 66 ]. This study highlights a strategy for balancing antibacterial activity and biocompatibility in cationic polymer design. Novel α-helical peptides incorporating both D- and L-type amino acids exhibited broad-spectrum antibacterial activity with low cytotoxicity. Their anti-biofilm activity was quantified using a real-time monitoring method (CoMIC), providing a new technical platform and drug candidates for biofilm-related infections [ 52 ]. Beyond direct membrane disruption, some α-helical peptides exert antibacterial effects by self-assembling into specific nanostructures. For instance, the peptide Nhar (Nap‑ D Nal‑Nal‑Har‑Har‑NH₂), designed via cationic amino acid scanning, self‑assembled into nanofibers in aqueous solution. These nanofibers physically entrapped bacteria, forming a “nanonet” that prevented bacterial spread and demonstrated significant efficacy against Gram‑positive bacteria like Staphylococcus aureus [ 67 ]. An enzyme-triggered polyelectrolyte complex formed by the self-assembly of α‑helical cationic peptides (polyglutamate derivatives) and phosphorylated poly(ethylene glycol)- b -poly(tyrosine) (PEG‑b‑PPTyr) could restore α-helical conformation in the presence of bacterial phosphatase, and achieve on-demand bactericidal activity while maintaining low hemolytic risk [ 68 ]. In clinical research, multiple antibacterial α-helical peptide candidates including PL-5 and WLBU2 (PLG0206) have entered clinical trials, demonstrating favorable efficacy and safety [ 69 ]. However, clinical application still faces challenges such as in vivo stability, susceptibility to enzymatic degradation, potential toxicity, and large‑scale production. Chemical modifications, including D‑amino acid substitution and peptide stapling, serve as effective strategies to enhance their stability and activity [ 70 ]. For instance, such approaches have been employed in the optimization of the EntV peptide [ 11 ]. Although some designed peptides exhibit low hemolysis and cytotoxicity, their immunogenicity requires rigorous evaluation [ 71 ]. Furthermore, large-scale production and cost remain critical hurdles, though advances in recombinant expression systems are helping to address these issues [ 72 ]. In summary, antibacterial α‑helical peptides exhibit diverse applications across preclinical and clinical stages, demonstrating direct anti‑inflammatory, antibacterial, and antifungal effects. Structural optimization including stapling, peptide fusion, and chemical modification has enabled the enhancement of their stability, target specificity, and bioactivity, thus advancing multiple drug candidates into clinical trials and highlighting their broad translational prospects. In the future, integrated multidisciplinary approaches combining deep learning‑assisted design, advanced chemical modification, and genetic engineering are expected to further enable α‑helical peptides to become a new powerful weapon against drug‑resistant infections [ 62 , 73 ]. Anticancer applications of α-helical peptides Cell membrane targeting and penetration mechanism α‑Helical peptides can selectively target and penetrate cancer cells by recognizing specific lipid components on cell membranes through their electrostatic properties and amphipathic structure. Cancer cell membranes typically exhibit higher levels of phosphatidylserine (PS), whereas normal cell membranes are predominantly composed of phosphatidylcholine (PC) [ 74 ]. For example, the synthetic anticancer peptide HB43 (FAKLLAKLAKKLL) is completely unstructured in aqueous solution but assumes α-helix conformation in the presence of PS-containing lipid bilayers, which serve as mimics of cancer cell membranes. This conformational switch promotes peptide internalization and membrane disruption, facilitated by specific interactions between the lysine side chains of HB43 and the carboxylate group of PS and/or the phosphate oxygen atoms of the targeted phospholipids [ 75 ]. Positively charged amino acid residues play a crucial role in peptide-membrane interactions. Through electrostatic interactions, cationic amphipathic anticancer peptides can preferentially bind to the negatively charged membranes of cancer cells. Subsequent hydrophobic insertion into the lipid bilayer can lead to membrane destabilization, pore formation, and ultimately cell necrosis [ 76 ]. Structural flexibility also modulates penetration efficiency. For example, the apolipoprotein E (apoE)-derived arginine-rich peptide A2-17, with its natural flexibility enabling multiple conformational adjustments, can facilitate transient pore formation in membranes, thereby enhancing membrane penetration and cellular uptake [ 77 ]. Furthermore, specific amino acid sequences and conformational regulation of the peptide also significantly influence the membrane penetration efficiency. Special structural motifs in the sequence are crucial for penetration performance. This principle is illustrated by antimicrobial peptides, for example, the central PXXP motif in the host defense peptide PMAP-23 accelerates its membrane penetration [ 78 ]. Incorporating analogous conformational regulatory motifs may thus represent a viable strategy to optimize the membrane penetration efficiency in designing anticancer peptides. In summary, α-helical peptides achieve selective recognition and penetration of cancer cell membranes through amphipathic charged characteristics, structural flexibility, and specific lipid-residue interactions. Insights gained from mimetic membrane systems and MD simulations provide a theoretical foundation and design principles for efficient and low-toxicity peptide drugs [ 79 , 80 ]. Induction of apoptosis and pyroptosis The molecular pathways by which peptides induce programmed cell death in cancer cells have emerged as a focal point in contemporary cancer therapeutics research. α-Helical peptides can trigger programmed cell death through distinct mechanisms, encompassing both classical apoptosis and the more recently characterized inflammatory cell death modality, pyroptosis. Apoptosis is initiated through intrinsic or extrinsic signaling cascades that activate mitochondrial or death receptor pathways, respectively. These pathways modulate BCL-2 family proteins—including BAX and BID—to increase mitochondrial membrane permeability, propagate death signals, and ultimately execute cellular demise. Accumulating evidence indicates that certain α-helical peptides can mimic or modulate the structure and function of BCL-2 family proteins to promote apoptotic signaling activation. For instance, “stapled” peptides incorporating hydrogen bond surrogate bridges designed to mimic the BAD BH3 motif not only effectively bind BCL-2 protein variants but also reverse drug resistance-associated structural alterations, thereby restoring apoptotic functionality [ 81 ]. Additionally, tetramer-mimicking peptides based on the C-terminus of p53 enhance reactive oxygen species generation and significantly induce apoptosis in mutant p53-harboring cancer cells through activation of FAS, caspase-8, and Bax pathways, while exhibiting no toxicity toward normal cells, thus demonstrating favorable selectivity [ 82 ]. Pyroptosis represents an inflammatory form of programmed cell death characterized primarily by Gasdermin D (GSDMD)-mediated pore formation in the plasma membrane, leading to cellular content release and inflammatory responses. Recent investigations have revealed that certain α-helical peptides can undergo environment-responsive conformational transitions—such as disorder-to-α-helix transformations—to form stable oligomers that selectively recognize negatively charged phospholipids on cancer cell membranes, thereby mediating pore formation and activating pyroptotic signaling pathways. Exemplifying this mechanism, a peptide derived from the MPT63 protein undergoes conformational switching in the acidic tumor microenvironment, generating protease-stable oligomers that initiate a cascade of pyroptotic events ranging from lysosomal membrane disruption to GSDMD-mediated plasma membrane perforation, ultimately culminating in cancer cell death [ 83 ]. This paradigm provides important insights for the rational design of novel environment-responsive peptide-based therapeutics. Furthermore, direct membrane penetration and subsequent membrane rupture with consequent intracellular content leakage constitute additional mechanisms by which peptides induce programmed cell death. For example, HMP-S7, an α-helical antileukemic peptide derived from human milk, selectively targets leukemia cells and induces lactate dehydrogenase release through membrane disruption, exhibiting dose-dependent cytotoxicity [ 84 ]. In parallel, walnut protein-derived peptides generated through in vitro simulated digestion have demonstrated not only anti-inflammatory properties but also the capacity to attenuate cellular apoptosis and inflammatory responses, highlighting the complex regulatory roles that peptides play in modulating the balance between cell survival and death [ 85 ]. Collectively, α-helical peptides induce cancer cell programmed death through multiple signaling pathways, encompassing classical apoptotic routes—such as modulation of BCL-2 family proteins, activation of caspase cascades, and p53-dependent mechanisms—as well as emerging pyroptotic pathways mediated by pore-forming proteins that execute plasma membrane destruction. These molecular mechanisms establish a robust theoretical foundation and promising application prospects for peptide-based drug design, particularly in the context of therapeutic strategies targeting drug-resistant malignancies, where α-helical peptide-based inducers of programmed cell death demonstrate substantial therapeutic potential and developmental opportunities [ 86 ]. Combination therapies and drug delivery systems Combination therapy of α-helical peptides with chemotherapeutic drugs or immune checkpoint inhibitors has emerged as an important strategy for enhancing anticancer efficacy. Their high binding affinity for target proteins can enhance drug targeting and bioactivity, while modulating the tumor microenvironment through immune cell modulation or potentiating immune responses to exert synergistic antitumor effects. Such combination therapy not only overcomes resistance to single drugs, but also reduces drug dosages, alleviates side effects, and improves patient tolerability. For example, co-administration of TGF‑β inhibitor nanoparticles modified with tumor‑penetrating α‑helical peptide A15 (A15‑LY‑NPs) and a vascular disrupting agent significantly enhanced drug accumulation at the tumors, leading to effective inhibition of lung and liver metastases [ 87 ]. Regarding drug delivery systems, nanocarriers modified with α-helical peptides offer advantages including high molecular stability and tunable surface functionality. For instance, the lipid-mimicking α-helical peptide Pm45, when combined with an RGD sequence, could spontaneously insert into lipid bilayers via a one‑step assembly, constructing an integrin-targeted delivery system. Its modified red blood cell membrane vesicles exhibited specific binding and efficient killing capacity toward breast cancer cells overexpressing αvβ3 integrin, enhanced DOX accumulation in tumors, and achieved therapeutic efficacy significantly superior to that of non-targeted carriers [ 88 ]. Similarly, pH-responsive α-helical peptides that adopt a random coil conformation at neutral pH but fold into α-helix in the acidic tumor microenvironment can achieve selective penetration into tumor cells while minimizing toxicity to normal cells [ 79 ]. Acid-responsive α-helical polypeptide-based nanoparticles (BINP) could insert into cell membranes and expose bisphosphonate motifs in the acidic tumor microenvironment, inducing mineralized barrier formation and inhibiting osteosarcoma growth and metastasis (Fig. 4 a) [ 89 ]. Fig. 4. Open in a new tab Anticancer applications of α-helical peptides. ( a ) Suppression of osteosarcoma progression by TME-responsive polypeptide-based BINP [ 89 ]. Copyright 2023, John Wiley & Sons. ( b ) Preparation of DD-H/P NCs: DOX was encapsulated in the inner cavity of DPP, followed by complexation with siPKM2 via electrostatic interactions, and further decorated by HA [ 90 ]. Copyright 2021, Elsevier. BINP: biomineralization-inducing nanoparticle; DOX: doxorubicin; DPP: densely packed, guanidine-rich, spherical helical polypeptide; HA: hyaluronic acid; NCs: nanocomplexes; siPKM2: small interfering RNA targeting pyruvate kinase M2; TME: tumor microenvironment As biodegradable carriers, α-helical peptides are capable of effectively encapsulating or conjugating small-molecule drugs, nucleic acids, peptides, and proteins. For example, spherical guanidinylated helical peptide (DPP) could co-encapsulate DOX and small interfering RNA targeting pyruvate kinase M2 (siPKM2), reversing chemoresistance by inhibiting tumor glycolysis through silencing PKM2 (Fig. 4 b) [ 90 ]. However, the development of effective in vivo delivery systems requires further optimization to ensure efficient and precise targeting of lesion tissues while minimizing nonspecific distribution and side effects. Photosensitizers/sonosensitizers and stimulator of interferon genes (STING) agonists were conjugated to biodegradable polypeptides and co-assembled with charge-modified polypeptides to construct a library of spatiotemporally regulated STING nano-adjuvant (SNA). Under laser or ultrasound stimulation (i.e., SNVac-L or SNVac-US), these systems effectively activated dendritic cells (DCs) and induced antigen-specific CD8 + T cell responses, thereby triggering antitumor immunity [ 91 ]. Additionally, light‑responsive polymer vesicles could undergo a conformational transition from β‑sheet to α‑helix under near‑infrared irradiation, enabling on‑demand co‑release of melittin and sorafenib, which induced immunogenic cell death and remodeled the tumor microenvironment [ 92 ]. Nevertheless, the stability and biodegradability of peptides often limit their in vivo half‑life and therapeutic efficacy. Chemical modifications such as cyclization and hydrocarbon stapling can enhance conformational stability and resistance to enzymatic degradation [ 15 ]. For example, although α-helical polycation PM maintained structurally stable in blood, RNase could penetrate the shell to degrade its internal mRNA. Substituting polylysine side chains with polyornithine significantly enhanced nuclease resistance, providing an optimized design for efficient systemic mRNA delivery [ 93 ]. In summary, α-helical peptides can mediate synergistic effects in combination therapy, while nanocarriers engineered around their structural features exhibit excellent stability and targeting efficiency. These advances are accelerating the translational progress of peptide-based therapeutics. By addressing key challenges in drug stability and specificity, these innovative systems provide a robust platform for future personalized cancer therapies. Immune regulation by α-helical peptides Immune cell activation and reprogramming α-helical peptides play a crucial role in the activation and regulation of immune cells, particularly T cells and macrophages, through diverse mechanisms. For T cells, the transcription factor FOXP3, essential for regulatory T cell (Treg) function, contains a homodimeric coiled-coil domain. A hydrogen bond-stapled peptide (SAH-FOXP3) was designed on this structure, which specifically blocks FOXP3 protein-protein interactions, thereby inhibiting Treg-mediated immunosuppression and enhancing antitumor immune responses [ 94 ]. For macrophages, the Sm16 peptide secreted by Schistosoma mansoni binds to macrophages via its amphipathic α-helix. Upon endocytosis, it elicits a weak pro-inflammatory signal while simultaneously inhibiting lipopolysaccharide (LPS)-induced inflammatory cytokine production. Transcriptomic analysis revealed that Sm16 primarily modulates the PPAR and LXR/RXR signaling pathways by altering macrophage metabolism of fatty acids, cholesterol, and glucose, thereby influencing their polarization state. This suggests that α-helical peptides can regulate immune cell function not only through direct interactions but also via metabolic reprogramming [ 95 ]. The metabolic shifts induced by helical peptides are generally reversible, and after discontinuation, the effects subside as the drug is cleared from the body. However, the speed and extent of this reversibility depend on the specific peptide structure, the specific target of action, and whether long-term epigenetic alterations or tissue damage have been caused. Beyond designed peptides, naturally occurring α‑helical AMPs exhibit immunomodulatory functions. Human Leucine-Leucine-37 (LL37), for instance, binds to nucleic acids to promote their recognition by immune cells, inducing type I interferon (IFN-I) expression and activating innate immunity. Specific residues on its hydrophilic‑hydrophobic surface determine binding to the scavenger receptor SR‑B1, thereby regulating the inflammation-induction function [ 96 ]. Furthermore, α-helical structures are integral to the functional domains of many immunoregulatory proteins. Chicken chemokine CX3CL1, featuring unique α-helices and disulfide bonds, promotes macrophage and T cell migration, induces pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IFN-β, and interleukin (IL)-6, and activates MAPK, NF-κB, and JAK/STAT pathways [ 97 ], underscoring the structural importance of the α-helical in immune signaling. In summary, α-helical peptides modulate immune cell function through diverse mechanisms, including regulating key transcription factors, reprogramming cellular metabolism, promoting immune recognition and nucleic acid sensing, and modulating cell migration and inflammatory cytokine expression. These insights provide a solid foundation for their application in immunotherapy and vaccine design. Anti inflammatory mechanisms α-helical peptides can exert anti-inflammatory effects through multiple pathways, primarily involving the suppression of inflammatory cytokine release and modulation of key signaling cascades. For instance, α-helical peptides derived from walnut protein digests can inhibit the expression of vascular endothelial growth factor (VEGF), 5-hydroxytryptamine (5-HT), and pro-inflammatory factors (e.g., TNF‑α) in LPS-induced human colonic epithelial cells by stably binding to target proteins, thereby alleviating apoptosis and inflammation [ 85 ]. Apolipoprotein A-I mimetics, as classical amphipathic α-helical peptides, when chronically expressed in the liver, can suppress IFN-α-mediated inflammation by inhibiting pathways related to pathogen-recognition receptors, natural killer cells, DCs, and Th1 responses, while activating LXR/RXR and PPARα/γ nuclear receptors [ 98 ]. Similarly, the plant-derived α-helical peptide PS77 reduced the expression of IL-8 and matrix metalloproteinase 3 (MMP-3) in a keratinocyte inflammation model and systemically downregulated inflammation-related genes by modulating CHRNA7 and CXCR5 within the BMP and TGF-β pathways [ 99 ]. A prominent mechanism involves the sequestration of pro‑inflammatory damage‑associated molecular patterns (DAMPs). For instance, spherical guanidylated α-helical polypeptides can stably bind to cell-free DNA (cfDNA), blocking its interaction with endogenous proteins (e.g., LL37), inhibiting toll-like receptor 9 (TLR9) activation and subsequent immune cell stimulation, reducing TNF-α and IL-6 levels, and alleviating inflammation in systemic lupus erythematosus models [ 100 ]. Furthermore, some peptides, such as the designed α-helical antimicrobial peptide P6.2, displayed potent anti-inflammatory effects both in vitro and in vivo, alleviating inflammation in a murine acute lung infection model, owing to their advantageous structural features [ 101 ]. The piscidin family of fish-derived AMPs possesses conserved amphipathic and cationic characteristics, which enhance stability and membrane affinity to modulate host immune responses and suppress pro-inflammatory cytokine production, thereby maintaining stable anti-inflammatory activity in high-salt and heavy-metal environments [ 102 ]. Structural stabilization of α-helical peptides does not merely increase half-life and cellular uptake; rather, it fundamentally enhances immunomodulatory efficacy by maintaining bioactive conformations. The prolonged half-life and improved cellular uptake are inevitable consequences of structural stabilization, with the three factors forming a functionally synergistic network: stable conformation ensures immune target recognition, metabolic stability guarantees effective exposure time, and membrane permeability enables intracellular target engagement. Therefore, in immunotherapeutic peptide design, structural stabilization should be regarded as a core strategy rather than merely a means of pharmacokinetic optimization. In summary, the anti-inflammatory mechanisms of α-helical peptides include: (1) direct inhibition of pro-inflammatory cytokine expression; (2) modulation of key signaling pathways such as TGF-β, BMP, PPAR, and LXR/RXR; (3) interference with immune cell activation and inflammatory mediator release; and (4) enhancement of targeted anti-inflammatory efficacy by improved stability and membrane affinity. The convergence of these actions makes α‑helical peptides promising candidates for treating inflammatory disorders. Vaccine engineering and immunotherapeutic potential Owing to their structural stability, predictable side‑chain presentation, and biocompatibility, α-helical peptides serve as excellent platforms for vaccine design and immunotherapy. In vaccine development, the co-assembly of α-helical peptides with antigenic epitopes and lipid moieties can generate self-adjuvanting vaccine carriers. For instance, a self-adjuvanting vaccine against Group A Streptococcus (GAS) was constructed by physically mixing a cyclic decapeptide scaffold bearing the B-cell epitope J8, the universal T-helper epitope PADRE, and a lipid tail. This formulation induced high titers of J8-specific IgG with broad-spectrum bacterial phagocytic activity in mice. The immunogenicity depended on the exposed C-terminus of the epitope, the lipid anchor, and the α-helical structure, which collectively facilitated the self-assembly and immunoreactivity of vaccine particles [ 103 ]. In multiepitope vaccines, α-helical peptide segments ensure structural stability of vaccines (with 12%-32% helical regions) and, as suggested by molecular docking, mediate high-affinity binding to TLR-4 and TLR-5, thereby enhancing immunogenicity and protective efficacy [ 104 , 105 ]. Lipidation further augments these effects. Conjugation of cholesterol to GAS epitopes promoted α‑helix‑driven self-assembly into nanoparticles, which, upon immunization, induced higher antibody titers and superior phagocytic activity compared to conventional adjuvants, with an excellent safety profile (Fig. 5 a) [ 106 ]. Self-assembling α-helical peptide nanoparticles represent another promising platform. For example, VADEX-pro nanoparticles based on an α-helical fusion protein possessed high thermal stability and effectively promoted antibody affinity maturation, outperforming some clinical-stage adjuvants [ 107 ]. Comparative studies showed that α-helical nanofibers presenting CD4 + T-cell epitopes were more effective than their β-sheet counterparts in activating follicular helper T (Tfh) cells and germinal center B cells, thereby enhancing antibody titers and affinity [ 108 ]. Fig. 5. Open in a new tab Vaccine engineering and immunotherapy with α-helical peptides. ( a ) Superior antibody induction using an α-helical lipopeptide compared to conventional adjuvants [ 106 ]. Copyright 2024, Elsevier. ( b ) Inhibition of cfDNA-induced inflammation by synthetic polypeptides through disruption of inter-nucleic acid spacing to TLR9 [ 110 ]. Copyright 2024, Springer Nature. ctDNA: calf thymus DNA; IFA: incomplete Freund’s adjuvant; IL-1β: interleukin-1β; IL-6: interleukin-6; LL37: Leucine-Leucine-37; LP1: lipopeptide; NA: nucleic acid; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; PADRE: pan DR-biding epitope, AKFVAAWTLKAAA; TLR9: toll-like receptor 9; TNF: tumor necrosis factor In cancer immunotherapy, the α-helix provides an ideal scaffold for designing T-cell receptor mimics (TCRm). The regular side‑chain projection allows precise mimicry of TCR complementarity-determining region (CDR) loops, enabling high-affinity binding to peptide-major histocompatibility complexes (pMHC). An α-helical TCRm targeting the NY-ESO-1 epitope exhibited nanomolar affinity with a natural TCR-like binding mode, effectively reducing off-target risks [ 109 ]. Beyond stimulation, α-helical peptides can also function as efficient cfDNA scavengers, blocking cfDNA-mediated inflammatory signaling pathways to restore immune homeostasis and suppress aberrant immune activation, particularly in autoimmune diseases (AIDs). Mechanistically, while natural LL37-nucleic acid complexes activate TLR9 due to optimal spacing, synthetic peptide-nucleic acid complexes (e.g., PEG-TK-NP Arg -NA) formed condensed structures that sterically hinder TLR9 aggregation and activation, thereby inhibiting autoimmune inflammation (Fig. 5 b) [ 110 ]. Material innovations have further advanced this strategy. For example, acid-responsive polyion complex vesicles (PICsomes) were assembled from PEGylated polypeptide with guanidine side chains (PEG-PG) and cis -aconitic anhydride-modified poly- L -lysine (PC), simultaneously achieving cfDNA scavenging by PEG-PG and immunosuppression via co-delivered methotrexate [ 111 ]. To overcome limitations like binding saturation and potential cfDNA release, an inflammation-activatable nanoscavenger was engineered by conjugating a cfDNA-cleaving moiety (Cyclen-Zn). This system sustainably inhibited TLR9 activation and restored immune homeostasis in inflammatory bowel disease (IBD) mice [ 112 ], offering a translationally promising avenue for clinical AID treatment. α-Helical peptide immunomodulation is dictated by precise structural determinants that dichotomize pro-inflammatory and tolerogenic activities. Inflammatory potential correlates with robust amphipathicity—manifest as expansive hydrophobic faces with high hydrophobic moment—and dense cationic charge distributions. Critically, select pro-inflammatory peptides (e.g., LL-37) self-assemble into supramolecular fibrillar networks that template double-stranded DNA into periodic immunocomplexes, nanocrystalline architectures that potently activate TLR9 to transform subthreshold nucleic acid recognition into potent immune activation. In contrast, tolerogenic peptides feature moderate amphipathicity and charge equilibration, utilizing stimulus-dependent helical folding or selective membrane interactions to exert immunosuppressive effects. For example, the PSMα3 peptide has been shown to penetrate and modulate human monocyte-derived dendritic cells, inhibiting their pro-inflammatory maturation and antigen uptake, which in turn promotes the differentiation of Tregs, thereby establishing immune tolerance. In conclusion, α‑helical peptides, as vaccine adjuvants and immunomodulators, leverage their structural robustness and design flexibility to show broad promise in peptide vaccines, self‑assembling platforms, cancer immunotherapy, and autoimmune therapy. Future interdisciplinary efforts integrating structural biology, immunology, and materials science will be crucial to drive their clinical translation. Applications of α-helical peptides in tissue engineering and regenerative medicine Design and functionalization of peptide-based scaffolds Owing to their excellent biocompatibility, tunable functionality, and stable secondary structure, α-helical peptides have emerged as promising materials for fabricating tissue‑engineering scaffolds. Their ordered conformation can provide cells with a natural extracellular matrix (ECM)-like microenvironment, thereby promoting cell adhesion, proliferation, and differentiation. α-helical peptide scaffolds are generally biocompatible, biodegradable, and are unlikely to trigger immune reactions when applied in vivo. For example, the neutral helical peptide L -P(EG 3 Glu) functions as a low-immunogenicity alternative to PEG, enabling safe repeated administration in rats (Fig. 6 a) [ 113 ]. These peptides can self‑assemble into multiscale structures (nanometer to micrometer), creating dynamic, tissue-mimetic microenvironments [ 114 ]. To promote cell adhesion and proliferation, integrin‑binding sequences such as RGD and IKVAV are often incorporated into α-helical scaffolds, enhancing cell attachment and survival via integrin-mediated signaling. For example, conjugating a VEGF-mimetic peptide to polycaprolactone electrospun fibrous scaffolds via thiol-ene click chemistry enhanced hydrophilicity, angiogenic capacity, and endothelial cell adhesion, thereby promoting vascular regeneration and tissue repair [ 115 ]. Furthermore, chemical modifications can further tailor scaffold properties. Histidine-containing peptide amphiphile nanofibers can chelate trace metal ions (Zn 2+ , Cu 2+ , Mn 2+ ), thereby modulating neural cell adhesion and morphological differentiation to promote neuronal growth [ 116 ]. Similarly, co-assembling nanocellulose with bioactive short peptides (e.g., Nap-HAVDI) yielded composite hydrogels with enhanced mechanical strength and cell adhesion [ 117 ]. Fig. 6. Open in a new tab Peptide scaffolds for tissue repair and regeneration. ( a ) Schematic diagrams illustrating the distinct proteolytic fates of L -P(EG 3 Glu) n and DL -P(EG 3 Glu) n [ 113 ]. Copyright 2024, KeAi Communications. ( b ) Modulation of the angiogenic switch using sulfono-γ-AApeptide mimics of VEGF-A [ 121 ]. Copyright 2022, American Chemical Society. VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor In summary, α-helical peptide scaffolds can form stable three-dimensional nanostructures through self-assembly, be functionalized with cell‑adhesive motifs to direct cellular behavior, and have their properties finely tuned through chemical modifications. These features enable them to effectively recapitulate key aspects of the native ECM, offering a versatile platform for tissue engineering [ 118 ]. Mechanisms for promoting tissue repair and regeneration α-helical peptides facilitate tissue repair and regeneration by orchestrating key processes such as angiogenesis, cell migration, and ECM remodeling. Angiogenesis is essential for supplying oxygen and nutrients to repair sites. α-helical peptides can specifically bind to cell surface receptors, activating downstream pathways like PI3K/Akt and MAPK to promote endothelial cell proliferation, migration, and regulate the expression of VEGF and its receptors, thereby enhancing neovascularization and tissue perfusion. Regarding cell migration, α-helical peptides can promote directional cell migration toward injured regions by regulating cytoskeletal dynamics and the expression and activity of adhesion molecules (e.g., integrins). This enhances cell-ECM interactions and facilitates chemokine‑guided recruitment, creating a pro‑migratory microenvironment [ 119 ]. During the tissue-remodeling phase, α-helical peptides participate in ECM degradation and reconstruction by modulating the balance between MMPs and their tissue inhibitors (TIMPs). This controlled proteolysis removes damaged matrix while promoting deposition of new collagen and elastin, restoring tissue integrity and mechanical function [ 120 ]. Furthermore, peptides can directly stimulate fibroblasts to synthesize ECM components, enhancing tissue strength and elasticity. Through these multifaceted mechanisms, α-helical peptides effectively coordinate the complex cascade of tissue repair, demonstrating significant potential for regenerative medicine. Clinical applications and future perspectives Leveraging their structural designability, biocompatibility, and precise bioactivity, α-helical peptides show broad translational potential in tissue engineering and regenerative medicine, with applications spanning vascular, bone repair, neural regeneration, and wound healing. In vascular regeneration, sulfono-γ-AApeptide sequences V2 and V3 selectively bind to vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2, enabling bidirectional regulation of angiogenesis (Fig. 6 b). While V2 acts as an agonist to stimulate vessel growth, V3 functions as an antagonist, offering a strategy to either promote revascularization in ischemic diseases or inhibit pathological angiogenesis in tumors [ 121 ]. In bone repair, synthetic helical peptides combined with bioceramics (e.g., hydroxyapatite) and stem cells can synergistically promote osteogenic differentiation and accelerate bone defect healing, with several approaches advancing toward clinical evaluation. For neural regeneration, a composite hydrogel (AFG/fSAP) integrating functionalized self-assembling peptide (fSAP) with aligned fibrin hydrogel (AFG) guided spinal cord regeneration, accelerating axonal regrowth, remyelination, and angiogenesis in preclinical models [ 122 ]. In wound healing, α‑helical peptides that combine antimicrobial and pro‑regenerative domains can effectively combat infection while promoting tissue repair with minimal cytotoxicity, a concept protected by relevant patents. Despite promising preclinical results, clinical translation faces hurdles including scalable synthesis, long‑term in vivo stability, and comprehensive safety assessment. Advances in synthesis, such as tetraalkylammonium carboxylate-initiated NCA polymerization in open aqueous environments, enable rapid, multigram‑scale production of complex block copolymers, addressing a key manufacturing bottleneck [ 123 ]. Building on the clinical progress of peptides like the enamel‑regenerating P11‑4 (Curodont ® ), α‑helical peptides are poised to offer novel solutions for tissue regeneration. Looking forward, computational and artificial intelligence (AI)-driven design tools (e.g., HelixGAN) will enable de novo creation of α-helical peptides with specific functions, vastly expanding the molecular design space [ 50 ]. Combining high-throughput screening with synthetic evolution will accelerate the discovery and optimization of highly efficient, low-toxicity peptides. Furthermore, integrating α-helical peptides with nanotechnology and advanced biomaterials will yield next‑generation smart scaffolds for tissue engineering. In summary, α-helical peptides hold significant value for clinical tissue engineering. By overcoming remaining translational challenges and harnessing AI-accelerated design, they are expected to yield a new generation of precise, effective regenerative therapies. The core biological function mechanisms of α‑helical peptides (Table 2 ) and their corresponding biomedical applications and clinical translation (Table 3 ) are summarized in the tables. Table 2. Core biological function mechanisms of α‑helical peptides Function area Key mechanism Structural basis and molecular events Physiological/pathological effects References Membrane interaction and disruption Electrostatic targeting and amphipathic insertion Cationic peptides binding to negatively charged lipids on bacterial/cancer cell membranes; hydrophobic residues inserting into lipid bilayers Membrane destabilization, pore formation, or lysis, leading to leakage/cell death [ 54 , 56 , 57 , 75 , 76 ] Conformation‑dependent recognition Active α‑helical conformation induced upon binding to target membranes (e.g., PS‑containing membranes) Achieving selective cancer cell killing (e.g., HB43 peptide) [ 75 ] Immunomodulation Direct immune cell modulation Blocking key protein-protein interactions (e.g., SAH‑FOXP3 inhibiting Tregs); reprograming macrophage metabolism (e.g., Sm16) Relieving immunosuppression, regulating inflammatory state [ 94 , 95 ] Pattern recognition receptor modulation Acting as adjuvant binding TLR4/5; or scavenging cfDNA, inhibiting TLR9 overactivation Enhancing vaccine immune response; treating autoimmune diseases (e.g., SLE) [ 100 , 103 , 106 , 110 – 112 ] Innate immune activation Binding nucleic acids (e.g., LL‑37), promoting production of type I interferon and other cytokine Enhancing host anti‑infection and anti‑tumor immune surveillance [ 96 ] Tissue repair promotion ECM‑mimetic signaling Self‑assembly into hydrogel/nanofiber networks presenting cell‑adhesion signals (e.g., RGD) Promoting cell attachment, spreading, proliferation, and differentiation [ 114 , 116 ] Regeneration pathway modulation Activating VEGFR/PI3K/Akt pathway for angiogenesis; regulating MMPs/TIMPs balance, guiding ECM remodeling Promoting neovascularization, tissue repair, and regeneration [ 119 , 120 ] Growth factor mimicry Mimicking functions of VEGF to specifically activate its receptors (e.g., sulfono-γ-AApeptide) Precisely regulating angiogenesis (activation or inhibition) [ 121 ] Open in a new tab Table 3. Biomedical applications and clinical translation of α‑helical peptides Application field Specific direction/system Design features and functions Preclinical/clinical progress Key challenges and countermeasures References Anti‑infection therapy Direct antimicrobial/antifungal therapy Amphipathic helices disrupting microbial membranes; inhibiting/destroying biofilms (e.g., Dex‑G15E15) EntV effective in Candid a infection models; several AMPs in clinical trials Stability/toxicity: optimization via “stapling”, D‑amino acid modification [ 52 , 62 – 66 , 69 , 70 ] Multifunctional anti‑infective systems Combining with photodynamic therapy (e.g., PPa‑cP), imaging, or immune modulation Demonstrating synergistic efficacy in complex infection models Specificity: integration of targeting ligands or condition‑activated strategies [ 61 , 64 , 101 ] Anti-cancer therapy Membrane‑targeted direct killing Selectively recognizing cancer cell membranes (e.g., PS) to induce membrane lysis HB43 peptide effective in model systems and some cell models Enhanced selectivity: computational design to optimize charge/hydrophobicity distribution [ 75 , 76 ] Smart drug delivery systems pH/enzyme‑responsive conformational transformation for tumor‑targeted release (e.g., BINP, DPP) Significantly inhibiting tumor growth and metastasis in multiple tumor animal models Delivery efficiency: optimization of nanocarrier assembly and in vivo kinetics [ 79 , 88 – 90 ] Acting as STING agonist carrier or inducer of immunogenic cell death SNA library effectively activates T cell-mediated anti-tumor immunity in models Systemic toxicity: development of local administration or tumor microenvironment-activated formulations [ 91 , 92 ] Immunotherapy combination Self‑adjuvanting vaccine Helical structures promoting self‑assembly into nanoparticles, enhancing antigen presentation Inducing superior antibody responses compared to conventional adjuvants Immunogenicity control: fine‑tuning the immunostimulatory potency of peptides [ 103 , 106 – 108 ] Autoimmune disease treatment Acting as cfDNA nanoscavengers, inhibiting TLR9 pathway (e.g., PICsomes) Effectively alleviating inflammation in murine models of SLE, IBD Longevity and safety: development of capture/cleavage integrated scavengers [ 100 , 110 – 112 ] Tissue engineering Functional bio‑scaffolds Self‑assembly providing 3D support and integrating bioactive signals (e.g., RGD, VEGF‑mimic peptide) AFG/fSAP hydrogels promote spinal cord injury repair; bone‑repair peptides under clinical translation Mechanical properties and integration: composite with natural materials to match tissue needs [ 114 , 116 , 120 , 121 ] Wound-healing dressings Combining antimicrobial and pro‑regenerative functions to form multifunctional coatings or hydrogels Related technologies patented, advancing wound‑healing applications Scalable production: development of NCA polymerization for large‑scale manufacturing [ 122 ] Open in a new tab Conclusion α-Helical peptides represent a class of highly versatile biomolecules with immense potential in biomedical applications. Their stable secondary structure, predictable side-chain arrangement, and programmable functionality enable precise molecular engineering for diverse therapeutic and regenerative purposes. As highlighted in this review, α-helical peptides exhibit unique advantages and broad prospects across diverse applications, exerting potent antimicrobial and anticancer effects via targeted membrane interactions, modulating responses through specific cell signaling and receptor engagement, and serving as foundational building blocks for tissue‑engineering scaffolds that mimic the native extracellular matrix. Nevertheless, the path to clinical translation is confronted by several persistent challenges: (1) the high costs and scalability limitations of chemical synthesis; (2) susceptibility to rapid proteolytic degradation in vivo and short plasma half-life; and (3) potential immunogenicity and off-target toxicity requiring rigorous evaluation. To overcome these hurdles, current strategies are focused on: optimizing solid-phase synthesis and NCA polymerization processes to improve cost‑effectiveness and scalability; employing strategies such as cyclization “stapling” and unnatural amino acid incorporation to enhance metabolic stability; and employing computational modeling and deep learning for rational design to refine target specificity and safety profiles. Thus, a coordinated integration of structural optimization, rigorous functional validation, and thorough preclinical safety assessment is essential for successful clinical advancement. Looking forward, progress in α-helical peptide therapeutics will be driven by deeper interdisciplinary convergence. Innovations in synthetic chemistry provide the molecular foundation, computational and AI-guided design accelerates the discovery of high-performance sequences, while nanotechnology and biomaterials engineering enable the construction of sophisticated, responsive delivery systems. Collectively, these developments will propel α-helical peptides toward breakthrough applications in precision medicine (e.g., personalized cancer vaccines, targeted molecular therapies) and regenerative medicine (e.g., bioactive tissue scaffolds, intelligent repair materials). In summary, the field of α-helical peptides has progressed from fundamental structural insights to functional innovation and translational exploration. Sustained research efforts and a holistic “design-synthesis-evaluation-application” pipeline will be crucial to realizing their full potential, ultimately yielding a new generation of safer, more efficient peptide-based therapeutics and biomaterials for improved human health. Acknowledgements Not applicable. Abbreviations SPPS Solid-phase peptide synthesis ROP Ring-opening polymerization NCAs N -carboxyanhydrides AI Artificial intelligence MD Molecular dynamics PPO Polyphenol oxidase Q4As Quaternary α-arylated amino acids RCM Ring-closing metathesis ROS Reactive oxygen species H₂O₂ Hydrogen peroxide DOX Doxorubicin OFM Optically functional molecule ALP Alkaline phosphatase SFRP1 Secreted frizzled-related protein 1 CD Circular dichroism NMR Nuclear magnetic resonance SAR Structure–activity relationship AMPs Antimicrobial peptides PG Phosphatidylglycerol GAPDH Glyceraldehyde-3-phosphate dehydrogenase PS Phosphatidylserine PC Phosphatidylcholine apoE Apolipoprotein E GSDMD Gasdermin D STING Stimulator of interferon genes DCs Dendritic cells Treg Regulatory T cell LPS Lipopolysaccharide LL37 Leucine-Leucine-37 IFN-I Type I interferon TNF Tumor necrosis factor IL Interleukin VEGF Vascular endothelial growth factor 5-HT 5-hydroxytryptamine MMP-3 Matrix metalloproteinase 3 DAMPs Damage‑associated molecular patterns cfDNA Cell-free DNA TLR9 Toll-like receptor 9 GAS Group A Streptococcus Tfh Follicular helper T TCRm T-cell receptor mimics CDR Complementarity-determining region pMHC Peptide-major histocompatibility complexes AIDs Autoimmune diseases IBD Inflammatory bowel disease ECM Extracellular matrix VEGFR Vascular endothelial growth factor receptor fSAP Functionalized self-assembling peptide AFG Aligned fibrin hydrogel Author contributions Mengyuan Yin: Writing – original draft, Validation, Visualization, Investigation, Formal analysis, Data curation, Conceptualization. Fei Ding: Writing – review & editing, Supervision, Resources, Conceptualization. Guanghua Luo: Writing – review & editing, Resources. Miaomei Yu: Writing – review & editing, Funding acquisition, Supervision, Project administration, Conceptualization. Funding This work was supported by the National Natural Science Foundation of China (82201509), the Applied Basic Research Project of Changzhou (CJ20241106), the Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project (2024CZBJ012) and Changzhou Health Talents Overseas Training Project ( GW202503 ). Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors gave their consent for publication. Competing interests The authors declare that they have no competing interests. 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