A natural remedy: Kidney-targeting nanoplatform for photoacoustic imaging-guided three-in-one theranostics of rhabdomyolysis-induced acute kidney injury.

A natural remedy: Kidney-targeting nanoplatform for photoacoustic imaging-guided three-in-one theranostics of rhabdomyolysis-induced acute kidney injury - 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. 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Learn more: PMC Disclaimer | PMC Copyright Notice Mater Today Bio . 2026 Mar 28;38:103068. doi: 10.1016/j.mtbio.2026.103068 Search in PMC Search in PubMed View in NLM Catalog Add to search A natural remedy: Kidney-targeting nanoplatform for photoacoustic imaging-guided three-in-one theranostics of rhabdomyolysis-induced acute kidney injury Xuhui Zhao Xuhui Zhao a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China b Shanxi Medical University, Taiyuan, 030001, China Find articles by Xuhui Zhao a, b, 1 , Yarong Jin Yarong Jin a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China Find articles by Yarong Jin a, 1 , Yahong Han Yahong Han a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China Find articles by Yahong Han a, 1 , Jin Zhang Jin Zhang a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China Find articles by Jin Zhang a, 1 , Qi Zhang Qi Zhang b Shanxi Medical University, Taiyuan, 030001, China c The First Hospital of Shanxi Medical University, Taiyuan, 030001, China Find articles by Qi Zhang b, c , Shilei Ren Shilei Ren d College of Computer Science and Technology, North University of China, Taiyuan, 030051, China Find articles by Shilei Ren d , Juan Li Juan Li b Shanxi Medical University, Taiyuan, 030001, China Find articles by Juan Li b , Shijie Liu Shijie Liu b Shanxi Medical University, Taiyuan, 030001, China c The First Hospital of Shanxi Medical University, Taiyuan, 030001, China Find articles by Shijie Liu b, c , Jie Dong Jie Dong b Shanxi Medical University, Taiyuan, 030001, China Find articles by Jie Dong b , Jingmiao Wu Jingmiao Wu b Shanxi Medical University, Taiyuan, 030001, China Find articles by Jingmiao Wu b , Xiaojing Fu Xiaojing Fu a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China Find articles by Xiaojing Fu a , Ting Xu Ting Xu a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China Find articles by Ting Xu a, ⁎ , Jinghua Sun Jinghua Sun b Shanxi Medical University, Taiyuan, 030001, China c The First Hospital of Shanxi Medical University, Taiyuan, 030001, China Find articles by Jinghua Sun b, c, ⁎⁎ , Ruiping Zhang Ruiping Zhang a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China Find articles by Ruiping Zhang a, ⁎⁎⁎ Author information Article notes Copyright and License information a Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China b Shanxi Medical University, Taiyuan, 030001, China c The First Hospital of Shanxi Medical University, Taiyuan, 030001, China d College of Computer Science and Technology, North University of China, Taiyuan, 030051, China ⁎ Corresponding author. [email protected] ⁎⁎ Corresponding author. Shanxi Medical University, Taiyuan, 030001, China. [email protected] ⁎⁎⁎ Corresponding author. Shanxi Provincial People's Hospital (Affiliated to Shanxi Medical University), Taiyuan, 030012, China. [email protected] 1 The first four authors contributed equally to this work. Received 2025 Aug 30; Revised 2026 Feb 27; Accepted 2026 Mar 24; Collection date 2026 Jun. © 2026 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMC Copyright notice PMCID: PMC13087793  PMID: 42006735 Abstract The high lethality of acute kidney injury (AKI) and the lack of safe and effective theranostic strategies pose significant challenges in clinical practice. Natural remedies are emerging as a promising alternative approach to alleviate AKI. Herein, we develop a novel kidney-targeting nanoplatform, MNPC@SC, which is engineered for pH-responsive drug release. Concretely, MNPC@SC encapsulates the natural bioactive ingredients curcumin (Cur) and melanin nanoparticles (MNPs) within a sialic acid (SA)-crosslinked chitosan shell, ensuring active renal targeting and optimal drug delivery via the electrostatic interactions between SA and chitosan. The acidic microenvironment of AKI triggers the responsive degradation of the MNPC@SC, further enabling the controlled release of MNPs and Cur specifically within the injured kidneys. The released MNPs and Cur achieve highly effective anti-inflammatory, anti-apoptotic, and anti-oxidant treatment, while MNPs serve as a contrast agent for photoacoustic (PA) imaging to self-monitor the drug distribution. To sum up, this pH-responsive targeting nanoplatform, MNPC@SC, as a new natural remedy, is believed to achieve efficient PA imaging-guided three-in-one synergistic therapy for AKI, which may pave the way for exploring highly efficient and safe theranostic strategies for severe kidney injury. Keywords: Acute kidney injury, MNPs, Kidney-targeting, Anti-oxidant, Anti-inflammation Graphical abstract A kidney-targeting nanoplatform, MNPC@SC, is developed for pH-responsive release of natural curcumin and melanin in the acidic AKI microenvironment. It offers a triple-action therapy (anti-inflammatory, anti-oxidant, anti-apoptotic) and self-monitored photoacoustic imaging via melanin, constituting a natural theranostic strategy against AKI. Open in a new tab 1. Introduction Rhabdomyolysis (RM) is a serious clinical syndrome that is characterized by damage to skeletal muscle tissues and leakage of myoglobin into the bloodstream [ 1 ]. One of the most prevalent complications of RM is acute kidney injury (AKI), which can result in life-threatening symptoms such as water and electrolyte imbalances, azotemia, and reduced urinary output [ 2 , 3 ]. Excess myoglobin is recognized as one of the key pathological characteristics of RM-induced AKI. It is stuck in the renal tubules to form tubular casts, subsequently phagocytized by lysosomes, and broken down to produce abundant reactive oxygen species (ROS) or reactive nitrogen species (RNS) via the Fenton reaction induced by the released iron ions, thus leading to severe oxidative stress, inflammatory injury, or even apoptotic damage to renal tubular cells [ 4 , 5 ]. Unfortunately, there is no effective medication available for AKI, and many agents used in supportive care are clinically nephrotoxic [ 6 ]. It is thus imperative to develop a safe and effective theranostic strategy aimed at reducing oxidative stress and inflammatory damage in RM-induced AKI. Natural remedies, including Chinese traditional medicines and natural active ingredients, have unparalleled superiority in preventing and treating AKI due to their low toxicity, high efficacy, and excellent loading capacity [ 7 , 8 ]. Curcumin (Cur), known as the “wonder drug of the future”, is a natural phenolic compound derived from the Curcuma longa plant. It has a variety of biological properties, including anti-inflammatory, anti-apoptotic, anti-oxidant, immunomodulatory, and neuroprotective effects, which assist to prevent AKI and restore the function of renal tubular epithelial cells [ [9] , [10] , [11] , [12] ]. However, its biomedical applications are hindered significantly by poor water solubility, rapid metabolism, low intestinal absorption efficiency, and limited bioavailability in vivo [ 13 ]. Inspiringly, the emerging nanotechnology has opened up new avenues for exploring safe and effective nano-drug delivery systems, which improve the bioavailability and therapeutic effects, thus offering a promising alternative for AKI [ [14] , [15] , [16] , [17] ]. Currently, various nanomaterials, including chitosan, nanogels, and polymeric micelles, have been reported for nano-Cur delivery [ [18] , [19] , [20] ]. It is worth mentioning that melanin nanoparticle (MNP), a natural pigment found in many living species, has been recognized as a therapeutic nanoplatform owing to its excellent biocompatibility, biodegradability, water-solubility, near-infrared absorbance, intrinsic photoacoustic (PA) signal, and binding performance with facile functional groups [ 21 , 22 ]. Moreover, it exhibits broad-spectrum scavenging activity against multiple toxic reactive oxygen/nitrogen species (RONS), giving it promising therapeutic effects in AKI disease related to oxidative stress [ 23 , 24 ]. Additionally, the aromatic nature of MNPs enables efficient Cur loading via π–π stacking interactions [ 25 , 26 ]. Therefore, nano-Cur co-loaded with MNPs could provide a promising approach to improve the efficiency of drug delivery, making it a preferential choice for reducing oxidative stress and alleviating inflammation of RM-induced AKI. Despite great therapeutic potential, the development of kidney-targeting theranostic nanoplatforms to achieve precise target imaging and image-guided anti-oxidant, anti-apoptotic, and anti-inflammatory synergistic therapy remains a challenging issue. In this study, we proposed a natural remedy strategy to achieve precise imaging-guided three-in-one (anti-oxidant, anti-apoptotic, and anti-inflammatory) therapy for RM-induced AKI. To this end, we developed a novel dual kidney-targeting nanoplatform, denoted as MNPC@SC. This nanoplatform was constructed using MNPs as the drug carrier, which were loaded with the anti-inflammatory agent Cur and then encapsulated in the sialic acid (SA)-cross-linked chitosan shell ( Scheme 1 ). Notably, SA modification enabled specific binding to E-selectin on injured endothelial cells while reducing nonspecific adsorption in the AKI mice model. Chitosan played a dual functional role in the nanoplatform: on the one hand, it facilitated kidney-targeting drug delivery through specific binding to megalin receptors on renal tubular epithelial cells [ [27] , [28] , [29] ]; on the other hand, the unique pH-responsive dissolution property of SA-cross-linked chitosan shell under acidic conditions facilitated the responsive decomposition of the MNPC@SC, resulting in the effective release of Cur in the acidic environment of urine in AKI, which further supported application in smart nanomedicine. Above these mechanisms collectively triggered a dual kidney-targeting strategy for optimized drug delivery [ [30] , [31] , [32] ]. The released Cur was utilized to explore its combined therapeutic effects with MNPs for AKI. Additionally, the MNPs specifically illuminated the kidney as an excellent PA imaging agent to track the accumulation of MNPC@SC. To sum up, this pH-responsive kidney-targeting nanoplatform MNPC@SC is believed to be an innovative attempt to achieve efficient PA imaging-guided anti-oxidant, anti-apoptotic, and anti-inflammatory therapy for AKI, which provides a new natural remedy for precise theranostics of severe kidney injury in the clinic. Scheme 1. Open in a new tab Schematic illustration of the MNPC@SC preparation and PA imaging-guided anti-oxidant, anti-apoptotic, and anti-inflammatory synergistic therapy for AKI. 2. Materials and methods 2.1. Chemicals All agents were obtained from commercial suppliers without further purification. Melanin was obtained from Sigma-Aldrich (St Louis, MO, USA). Amine-PEG 5000 -amine (NH 2 -PEG-NH 2 , 5 kDa) was purchased from Rulxl Biological Technology Co., Ltd (Xi'an, China). Sialic acid (SA), glycol chitosan, and Curcumin (Cur) were purchased from Macklin Biochemical CO., Ltd (Shanghai, China). N-Hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) were obtained from Energy Chemical (Shanghai, China). 2,2-Diphenyl-1-picrylhydrazyl (DPPH) was purchased from TCI Development Co., Ltd (Shanghai, China). Total anti-oxidant capacity assay kit (ABTS method) was purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). The CCK-8 Assay Kit was provided by Servicebio Technology CO., Ltd (Wuhan, China). Glycerol, hydroxyl free radical scavenging capacity assay kit, superoxide dismutase (SOD), Malondialdehyde (MDA), and Catalase (CAT) assay kit were purchased from Solarbio Science & Technology Co., Ltd (Beijing, China). 2.2. Preparation of MNPC nanoparticles The PEGylated ultrasmall melanin nanoparticles (MNPs) were prepared and functionalized with NH 2 -PEG5000-NH 2 according to our previous work. Then, the curcumin ethanolic solution (5 mg/mL) was dropwise added to the MNPs aqueous solution under vigorous stirring, maintaining a feed ratio of 1:5 (Cur: MNP). After overnight stirring, the mixture was concentrated by rotary evaporation at 60 °C to remove free Cur. The resulting product was subsequently purified with ethanol washing (absolute ethanol, 99.8%) and centrifugation (8000 rpm, 10 min) three times, followed by resuspension in deionized water to obtain the MNPC nanoparticles. 2.3. Preparation of MNPC@SC nanoparticles The carboxyl groups of SA were easily conjugated with amine groups of the MNPs via the EDC/NHS reaction. Briefly, SA (10.0 mg), EDC (10.0 mg), and NHS (10.0 mg) were co-dissolved in deionized water (5 mL) and stirred for 3 h to activate the carboxy groups of SA. Then, the MNPC solution (containing 10 mg of MNPs) was added to the activated SA mixture and stirred overnight at room temperature. The resulting product was purified by ultrafiltration centrifugation (3500 rpm, 10 min) with three washing cycles to remove excess SA, EDC, and NHS. Finally, glycol chitosan aqueous solution (1 mg/mL) was added to the above SA-functionalized MNPC solution and magnetically stirred overnight. The final MNPC@SC nanoparticles were concentrated with an ultrafiltration centrifuge filter (MWCO = 30 kDa, Millipore) at 3500 rpm for 10 min to remove the excess substance. 2.4. Characterizations of MNPC@SC nanoparticles We used a JEM-2100F transmission electron microscope (Tokyo, Japan) to investigate the shape and size of MNP, MNPC, and MNPC@SC nanoparticles. The dynamic light scattering and zeta potential of different nanoparticles were tested by a Nano-Zetasizer (Malvern, UK). The absorbance spectra were analyzed by UV-vis-NIR spectroscopy (UV-6100, MAPADA, Shanghai, China). Fourier-transform infrared (FT-IR) spectroscopy for the identification of the bonds of the above nanoparticles was obtained on a PerkinElmer Spectrum TWO spectrophotometer (Bruker). 2.5. Drug loading and release behavior in vitro The drug loading capacity (LC) and encapsulation efficiency (EE) of Cur were measured by UV-vis-NIR spectroscopy based on the absorbance at 430 nm. Then, the calculation formula of DL was displayed as follows: LC ( % ) = Weight of loaded drug / weight of drug loaded nanoparticles × 100 % EE ( % ) = Weight of loaded drug / weight of added drug × 100 % The release behavior of Cur in MNPC@SC was studied by the dialysis bag method in PBS at pH 7.4 and 5.5 for 48 h, and the concentration of Cur was also determined by the above UV-vis-NIR spectroscopy. At the indicated time points, a certain volume of release medium was withdrawn, followed by replacement with a fresh medium. The release and loading of Cur were qualified using UV-vis-NIR spectroscopy. 2.6. Cell experiments Cell culture . Renal tubular duct epithelial cells of rats (NRK-52E cells) were purchased from Shanghai Institutes for Biological Sciences and were cultured in DMEM/F12 medium containing 10% FBS and 1% penicillin-streptomycin at 37 °C under a 5% CO 2 containing atmosphere. Injury models of NRK-52E cells were stimulated by cobalt chloride (CoCl 2 ) in all experimental groups. Cytotoxicity assay . NRK-52E cells were seeded in 96-well plates at a density of 8 × 10 3 cells per well for overnight adherence. After that, the old medium was replaced with fresh DMEM/F12 medium containing MNPC@SC at various concentrations (0, 12.5, 25, 50, 100, and 200 μg/mL), followed by incubation for 12 h. Then, the dead cells were washed with PBS, and the remaining live cells were incubated in new medium containing 10% CCK-8 for 1 h in the dark. Finally, the absorbance of each well was measured at 450 nm and recorded using a microplate reader (SpectraMax Plus384). Cellular uptake study . NRK-52E cells were seeded in 6-well plates at a density of 1 × 10 4 per well and allowed to adhere for 12 h. The cells were then treated with FITC-labeled MNPC@SC (100 μg/mL) for 1, 4, and 6 h, followed by washing with PBS. After treatments, cells were collected, transferred to flow tubes, and resuspended in PBS (0.5 mL). Finally, the cellular uptake of MNPC@SC was assessed by flow cytometry (Beckman Coulter Ireland, Inc). Intracellular ROS detection . NRK-52E cells were pre-treated with CoCl 2 (400 μmol/L) for 24 h. After stimulation, cells were washed with PBS. Then medium containing MNP, MNPC, and MNPC@SC (100 μg/mL) was added to each well and incubated for 6 h. Subsequently, cells were incubated with 20 μM DCFH-DA in serum-free medium for 30 min. After washing three times, the green fluorescence signal intensity in each group was measured by fluorescence microscope (Olympus IX73) and flow cytometry. Mitochondrial membrane potential (MMP) analysis . As mentioned above, NRK-52E cells were pre-treated with CoCl 2 stimulation. After incubating with MNP, MNPC, and MNPC@SC (100 μg/mL) for 6 h. Then, JC-1 dye was introduced to stain the mitochondria. Finally, the level of MMP fluorescence signal was estimated using a fluorescence microscope. Cell apoptosis assay . NRK-52E cells were seeded into 6-well plates and supplied with CoCl 2 , followed by incubation with the above different agents. Cells were collected and stained with the Annexin V-FITC/PI apoptosis detection kit. Finally, cells were suspended in PBS and tested by flow cytometry. 2.7. AKI mice model All animal experiments were approved by the Institutional Animal Use and Care Committee in Shanxi Medical University (Approval No. 2022-025, Taiyuan, China). ICR mice (6-8 weeks old, male) were purchased from the Animal Center of Shanxi Medical University. The AKI mouse model was established according to the method reported by our group. Before establishing the AKI model, ICR mice were deprived of water for 15 h, and food was supplied. Then, 50% (v/v) glycerin solution was injected into the inner thigh muscles of mice at a dose of 8 mL/kg, gently massaged to promote absorption. After 24 h, the glycerin-induced AKI model was successfully established by histopathological examination and hematological measurement. 2.8. In vivo photoacoustic imaging Photoacoustic imagings of MNPC and MNPC@SC in the healthy and AKI model were captured by the Vevo LAZR-X PA imaging system at various time points (0, 3, 6, 9, 12, and 24 h post-injection). After intramuscular injection of glycerol, MNP, MNPC, and MNPC@SC with the same MNP content of 4 mg/kg were intravenously injected into AKI mice. And the same dose of MNPC@SC was injected into the normal mice as a control. The acquired images were analyzed using Vevo LAB 5.6.0 software. 2.9. Evaluation of therapeutic effect in vivo Mice were randomly divided into five groups: (1) Control (normal saline); (2) AKI (normal saline); (3) AKI + MNP (4 mg/kg); (4) AKI + MNPC (4 mg/kg); (5) AKI + MNPC@SC (4 mg/kg), n = 5. To ensure the therapeutic effect, mice were treated with different agents via tail intravenous injection for three consecutive doses. At 1 h post-glycerin induction, agents were given to AKI mice for the first time. During the course of treatment, different agents were given every 24 h. After injection for 72 h, the kidneys and blood in each group were collected for the following testing. Blood biochemical index . After the treatment of all mice, blood was collected by removing the eyeballs and allowed to clot at 4 °C for 1 h. By centrifugation at 4000 rpm for 10 min, serum was carefully collected to analyze the levels of blood urea nitrogen (BUN) and creatinine (CRE). Histological analysis, immunofluorescence, and immunohistochemistry staining . After treatments, kidney tissues of mice in each group were fixed with 4% paraformaldehyde. Then, after a series of operations including dehydration, embedding, sectioning, and staining for H&E, periodic acid-Schiff (PAS), Ly6G, MPO, TUNEL, and MCP-1. The resulting slices were imaged with a standing optical microscope. Inflammatory factors evaluation . About the size of a mung bean of kidney tissue was used to extract protein. Fresh kidney tissue homogenates were used to measure tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) levels by using ELISA kits. Detection of biomarkers . The SOD, MDA, and CAT levels of the extracted histone were determined with the assay kit (Nanjing Jiancheng Bioengineering Institute). 2.10. Biocompatibility assays High-dose MNPC@SC NPs (6.4 mg/mL) were intravenously injected into normal healthy mice. After the injection of 24 h and 72 h, blood samples were extracted to detect biochemical indicators such as BUN, CRE, alanine transaminase (ALT), and aspartate transaminase (AST). At the same time, major organs (heart, liver, spleen, lung, and kidney) were then fixed in 4% paraformaldehyde for H&E staining. 2.11. Statistical analysis All results were expressed as mean values ± standard deviation. Statistical significance was analyzed using one-way ANOVA. ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001, ns = not significant. 3. Results and discussion 3.1. Synthesis and characterization of MNPC@SC The ultrasmall PEGylated MNPs were synthesized according to our previous studies [ 33 , 34 ]. As presented in Fig. 1 A, the as-synthesized MNP had good dispersibility and even distribution with an average size of about 4 nm. Then, the Cur was bound onto MNP through π-π interaction to obtain MNPC nanoparticles [ 35 ]. The carboxyl groups of SA were then conjugated to the amine groups on the MNPC surface by a typical EDC/NHS reaction, followed by cross-linking with glycol chitosan by non-covalent interactions, such as electrostatic interactions, steric stabilization effects, and van der Waals forces. This final coating facilitated the resulting MNPC@SC nanoparticles with pH-responsive properties. The transmission electron microscopy (TEM) images in Fig. 1 B–C revealed an increasing size of MNPC with ∼18 nm and spherical-sized structure of MNPC@SC with an average diameter of ∼30 nm, respectively. Correspondingly, the average hydrodynamic diameter (HD) of MNPC@SC increased to ∼75.8 nm from ∼4.8 nm of MNP analyzed by dynamic light scattering (DLS) ( Fig. 1 D). And Cur loading caused the zeta potential of MNPC underwent a shift from −26.8 ± 3.0 (MNP) to −22.7 ± 1.7 mV (MNPC), and that of final product MNPC@SC was −7.2 ± 0.5 mV ( Fig. 1 E), which attributed to the successful preparation of sialic acid (SA)-cross-linked chitosan shell through electrostatic binding. Fig. 1. Open in a new tab Characterization of MNPC@SC NPs. TEM images and size distribution diagrams of MNP (A), MNPC (B), and MNPC@SC (C). (D) Particle size distribution of MNP, MNPC, and MNPC@SC. (E) Zeta potential of MNP, MNPC, and MNPC@SC. (F) FT-IR spectra of MNP, Cur, MNPC, and MNPC@SC. (G) UV–vis absorption of MNP, Cur, MNPC, and MNPC@SC. (H) PA imaging of MNPC@SC (inset: corresponding absorption intensity as a function of different concentrations). (I) In vitro release profile of Cur from MNPC@SC in PBS at pH 5.5 and 7.4. The scavenging property of MNPC@SC for ·OH (J), ABTS ·+ (K), and DPPH • (L). Data are expressed as the mean ± SD (n = 3). Furthermore, Fourier-transform infrared (FTIR) spectra were employed to confirm the successful encapsulation of Cur within the MNPC@SC. As shown in Fig. 1 F, the spectrum of MNPC displayed distinctive absorption peaks related to C-O-(CH 3 ) stretching vibration at 1187 cm −1 of Cur. Notably, other obvious characteristic peaks included the stretching vibration attributed to C=O at 1727 cm −1 of SA, and asymmetric vibration attributed to C=O at 1100 cm −1 of chitosan, confirming that MNPC were successfully modified by both SA and chitosan [ 32 ]. Simultaneously, the ultraviolet-visible (UV-vis) absorbance spectra of MNPC and MNPC@SC displayed distinct absorption peaks of Cur at 430 nm, suggestive of the successful integration of Cur into MNPC@SC ( Fig. 1 G). Remarkably, MNPC@SC remained well-dispersed and showed no signs of sedimentation, with a PDI maintained below 0.2, which demonstrated that the MNPC@SC exhibited excellent physiological stability and potential for prolonged blood circulation ( Figs. S1–S3 , Supporting Information). Based on the broad absorption spectrum of MNPC@SC covering the ultraviolet-visible and near-infrared windows, we further conducted the PA imaging performance of MNPC@SC across the concentration range of 0 to 800 μg/mL. The results showed a well-fitted linear relationship between the PA signal and the concentration of MNPC@SC, making it an ideal contrast agent for PA imaging in vivo ( Fig. 1 H). Additionally, we investigated the effect of pH on the responsive release of Cur from MNPC@SC ( Fig. 1 I). Compared with the neutral microenvironment, the cumulative release of Cur from the MNPC@SC in the acidic microenvironment (pH = 5.5) displayed a noticeable upward trend within 10 h, and reached its maximum release levels at 50 h, indicating the high sensitivity of MNPC@SC to the acidic microenvironment of AKI. The loading capacity and encapsulation efficiency of Cur in MNPC@SC were found to be 9.2 ± 0.8% and 66.5 ± 0.2%, following the calculation of the concentration standard curve. 3.2. Free radicals scavenging ability of MNPC@SC The onset and progression of AKI are closely linked to RONS overproduction, which can induce DNA damage, lipid peroxidation, and the oxidation of proteins [ 36 , 37 ]. ·OH, a highly active free radical found in living organisms, was selected to evaluate the reactive oxygen species (ROS) scavenging capability of MNPC@SC. As depicted in Fig. 1 J, MNPC@SC exhibited an excellent scavenging activity of ·OH in a concentration-dependent manner. At a concentration of 50 μg/mL of MNPC@SC, almost 60% of ·OH was scavenged. ABTS with potassium persulfate showed a blue color and a characteristic UV-vis absorption peak at 734 nm ( Fig. S4A , Supporting Information). MNPC@SC exhibited a concentration-dependent manner in quenching ABTS •+ , with a corresponding color change from blue to colorless in the solution. As shown in Fig. 1 K, MNPC@SC could scavenge over 90% of ABTS • at a concentration of 100 μg/mL, indicating its strong anti-oxidative properties . In addition, DPPH, a nitrogen radical containing multiple unpaired electrons, was employed to examine the reactive nitrogen species (RNS) scavenging activity of MNPC@SC, with the DPPH • ethanol solution showing a dark purple color and an absorption peak at 517 nm. The absorption peak consistently decreased with increasing concentrations of MNPC@SC in DPPH • solution, transitioning from purple to yellow ( Fig. S4B , Supporting Information). As presented in Fig. 1 L, MNPC@SC scavenged over 70% of the DPPH at a concentration of 100 μg/mL. Taken together, these results demonstrated that the MNPC@SC could achieve efficient and broad-spectrum scavenging against multiple RONS, thus enabling the promising potential to alleviate oxidative stress of the AKI. 3.3. Cytotoxicity, cellular uptake, and cytoprotection of MNPC@SC Inspired by the superior physicochemical features of MNPC@SC, we analyzed the cytotoxicity of MNPC@SC on a renal tubular duct epithelial (NRK-52E) cell line at different doses using the Cell Counting Kit-8 (CCK-8) assay. As seen in Fig. 2 A, NRK-52E cells did not exhibit any discernible cytotoxicity at all tested concentrations. Moreover, ROS-induced renal tubular cell damage during AKI was imitated by CoCl 2 , a chemical reagent that may efficiently trigger cell apoptosis. The CCK-8 assay revealed concentration-dependent cytotoxicity of CoCl 2 in NRK-52E cells. When the concentration of CoCl 2 was 400 μmol/L, the cell viability was reduced by approximately 50 % ( Fig. 2 B). Encouragingly, the NRK-52E cells treated with MNPC@SC upon CoCl 2 stimulation exhibited concentration-dependent cell proliferation, mainly consequent on the anti-oxidative property of MNPC@SC. When the concentration of MNPC@SC reached 100 μg/mL, the cell survival rate returned to almost 85% ( Fig. 2 C). Consequently, it was reasonable to select 100 μg/mL as the optimal concentration of MNPC@SC. Furthermore, flow cytometric analysis was employed to monitor the cellular internalization of fluorescein isothiocyanate (FITC)-labeled MNPC@SC. The increasing fluorescence signal in NRK-52E cells indicated the efficient cellular uptake of MNPC@SC over time, with maximum fluorescence intensity of 98% at 6 h ( Fig. 2 D). Fig. 2. Open in a new tab Cytocompatibility and in vitro therapeutic effects. (A) NRK-52E cell viability treated with MNPC@SC at different concentrations. (B) NRK-52E cell viability treated with CoCl 2 at different concentrations. (C) NRK-52E cell viability treated with MNPC@SC after CoCl 2 stimulation. (D) Flow cytometric analysis of cellular internalization for FITC-labeled MNPC@SC. (E) Fluorescence images of intracellular ROS and (F) quantitative analysis of the mean fluorescence intensity of ROS following MNP, MNPC, and MNPC@SC treatment. Scale bar = 100 μm. (G) Representative flow cytometric analysis and (H) quantitative flow cytometric results of the intracellular ROS production in each group. Data are expressed as the mean ± SD (n = 3). ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001. In view of the excellent ROS scavenging property of MNP and Cur, we investigated ROS levels in NRK-52E cells utilizing a 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. In Fig. 2 E–F, the CoCl 2 -stimulated group showed maximum fluorescence intensity compared to the control group, suggestive of the large amounts of ROS produced by the renal tubular epithelial cells. The intensities of the fluorescence signal in CoCl 2 -stimulated cells incubated with MNP, MNPC, and MNPC@SC were gradually decreased, with the MNPC@SC group lowest. Accordingly, consistent findings were obtained by flow cytometric analysis, evidently indicating the optimum ROS scavenging property of MNPC@SC ( Fig. 2 G–H). Overproduction of ROS could also directly activate inflammatory responses, which contributed to the production of pro-inflammatory cytokines [ 38 ]. Therefore, a series of key cytokines including TNF-α, IL-6, and IL-1β were analyzed by ELISA assay. As shown in Fig. S5 , CoCl 2 -induced AKI dramatically induced the overexpression of TNF-α, IL-6, and IL-1β. Notably, the MNPC@SC treatment group had the strongest ability to alleviate inflammation compared to MNP and MNPC, with the relative levels of TNF-α, IL-6, and IL-1β almost returning to normal values. To sum up, the above results demonstrated that MNPC@SC had good biocompatibility, targeting uptake, free radical scavenging activity, and good anti-inflammatory ability, which offered the possibility of further in vivo AKI therapy. The proper mitochondrial membrane potential (MMP), a critical indicator for assessing the physiological functions of mitochondria, is required for sustaining mitochondrial oxidative phosphorylation and cellular energy supply [ 39 ]. When cells undergo oxidative stress-induced damage, the mitochondria depolarize, resulting in a reduction in the red/green fluorescence intensity ratio. We evaluated the effect of MNPC@SC on cellular mitochondria by analyzing MMP alterations using JC-1 labeling ( Fig. 3 A). In the mitochondria of normal NRK-52E cells, JC-1 molecules aggregated and produced strong red fluorescence. In the CoCl 2 -stimulated group, JC-1 released from the mitochondria as a monomer emitted green fluorescence. The MNPC@SC group exhibited a marked decrease in green fluorescence in comparison to the MNP and MNPC groups, suggesting that the elevated ROS levels disrupted the mitochondrial membrane. To investigate the impact of different treatments on cellular apoptosis, we further performed flow cytometric analysis using an Annexin V-FITC/PI Apoptosis Detection Kit. As shown in Fig. 3 B and Fig. S6 , the proportion of both early and late apoptotic cells was 48.5% in the CoCl 2 -stimulated group. Notably, the percentages of apoptotic cells in the MNPC@SC group dropped drastically to 4.63% compared to 29.9% and 19.08% in the MNP and MNPC groups, respectively. Taken together, the above findings suggested unequivocally that the ROS scavenging property of MNPC@SC led to mitochondria protection, ultimately achieving excellent anti-apoptosis to alleviate AKI. Fig. 3. Open in a new tab In vitro anti-apoptosis effects. (A) Fluorescence images of JC-1 staining in NRK-52E cells following MNP, MNPC, and MNPC@SC treatments. Scale bar = 100 μm. (B) Flow cytometry detection of apoptotic NRK-52E cells in each group. 3.4. Biodistribution of MNPC@SC in mice Inspired by the exciting PA imaging property of MNPC@SC in vitro , we further evaluated the metabolism of MNPC@SC in the kidney by PA imaging in vivo . Initially, 50% glycerol was injected intramuscularly into dehydrated normal mice to establish a mouse model of rhabdomyolysis-induced AKI, and kidney PA imaging was then carried out. As illustrated in Fig. 4 , MNPC@SC exhibited superior accumulation in injured kidneys, with specific fluorescence signal enhancement observed in the kidneys of the AKI model group compared to the healthy control group. In addition, the MNPC@SC group showed significantly enhanced PA imaging signals in affected kidneys in contrast to both the MNP ( Fig. S7 , Supporting Information) and MNPC group, which offered compelling evidence that the modification of SA and glycol chitosan improved the targeting property of MNPC@SC. According to the quantitative analysis, the intensity of PA signals in the AKI model steadily increased over time and peaked at 6 h after intravenous administration ( Fig. S8 , Supporting Information), indicating that this was the optimum time point for MNPC@SC accumulation. In contrast, no distinct PA signals were seen in healthy mice. The findings indicated that MNPC@SC could be highly accumulated in the affected kidneys of AKI, thereby facilitating precise PA imaging-guided AKI alleviation. Fig. 4. Open in a new tab Representative PA images of kidneys at different time points (0, 3, 6, 9, 12, and 24 h) in healthy and AKI mice treated with MNPC and MNPC@SC. Furthermore, the in vivo pharmacokinetic behaviors of MNP, MNPC, and MNPC@SC have been analyzed ( Fig. S9 , Supporting Information). Ex vivo imaging system demonstrated significantly enhanced renal accumulation of MNPC@SC at 0, 3, 6, and 24 h post-injection in the AKI mice model compared to MNP and MNPC groups. Quantitative analysis revealed that the biodistribution of ICG-labeled MNPC@SC in renal accumulation initiated at 3 h post-injection, peaked at 6 h, and basically disappeared by 24 h. Hepatic uptake remained high at 24 h, which was mainly due to the capture of nanoparticles by the mononuclear phagocyte system in these organs; while only minimal pulmonary uptake was observed in select formulations; no detectable fluorescence signals were recorded in either heart or spleen tissues throughout the observation period. Notably, the MNPC@SC consistently showed strong renal fluorescence signals across all time points in AKI mouse model, demonstrating the excellent targeting ability to injured kidneys. 3.5. RM-induced AKI treatment To evaluate the therapeutic efficacy of MNPC@SC, the RM-induced AKI mice model was effectively constructed by the treatment scheme outlined in Fig. 5 A. Following glycerin induction, a total of five groups were randomly assigned: (1) Control, (2) AKI, (3) MNP, (4) MNPC, and (5) MNPC@SC. As seen in Fig. 5 B, the body weight of mice in the AKI group reduced significantly, whereas that of mice in the MNP and MNPC groups remained relatively stable throughout the treatment period. Notably, the body weight of the mice treated with MNPC@SC increased similarly to that of the control group. The blood urea nitrogen (BUN) and serum creatinine (CRE), as the representative indicators of renal function, were selected to evaluate the effect of different treatments on AKI. As shown in Fig. 5 C and D, the BUN and CRE levels of the AKI group were much greater than those of the control group, indicating that the model was successfully constructed. Remarkably, the MNPC@SC group had lower levels of CRE and BUN than the MNP and MNPC groups, suggesting that MNPC@SC could effectively restore renal function. Fig. 5. Open in a new tab Therapeutic effects of MNPC@SC in the AKI mice model. (A) Schematic diagram of the establishment and treatment in AKI mice. (B) Body weight changes of mice following different treatments. (C) BUN and (D) CRE levels of AKI mice in each group. (E) H&E staining images of kidneys in each group. Arrows indicate damaged kidney tubules, and asterisks indicate the formation of a cast. Scale bar = 50 μm. (F) PAS staining images of kidneys in each group. Red arrows indicate the shed renal tubular endothelium. Scale bar = 50 μm. (G) TUNEL staining images of kidneys in each group. Yellow arrows indicate the apoptotic positive cell. Scale bar = 50 μm. Data are expressed as the mean ± SD (n = 3). ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001. Moreover, pathological examinations were performed to assess the extent of kidney damage. As shown in Fig. 5 E, hematoxylin and eosin (H&E) staining of the affected kidneys revealed extensive casts and severe renal tubular epithelial cell detachment in AKI mice. These signs were partially alleviated in the MNP and MNPC groups, with near-normal cytoarchitecture and no obvious tubular necrosis found in the MNPC@SC group. The findings were also confirmed by PAS staining, which demonstrated the integrity of the tubular epithelium. In the AKI group, there was a considerable loss of renal tubular endothelium, indicative of severe injury to the renal tubules. Remarkably, renal tubular endothelium in the MNPC@SC group appeared almost intact ( Fig. 5 F). In addition, TUNEL staining displayed the lowest degree of apoptosis in the MNPC@SC group, which was close to that of the control group, suggesting that MNPC@SC could effectively prevent the large-scale apoptosis of renal cells, thus reducing the risk of renal failure ( Fig. 5 G). The molecular mechanism of apoptosis is triggered by protein-hydrolyzing enzymes belonging to the Caspase (cysteine protease) family. The progression of apoptosis occurs when inducible Caspases are cleaved and activated into Cleaved-Caspase-3. Caspase-3 is the most important terminal cleavage enzyme in the apoptotic process and has been reported to be positively associated with renal dysfunction [ 40 ]. The expression level of Caspase-3 was detected by immunohistochemistry ( Fig. S10 , Supporting Information). The results showed that the expression level of Caspase-3 was elevated in AKI mice. However, MNPC@SC treatment effectively reduced the expression of Caspase-3. Collectively, the above results indicate that MNPC@SC could effectively alleviate the renal injury with the greatest anti-apoptosis performance in vivo , thereby conferring renal protection. It is evidenced that inflammation usually accompanies and promotes renal tissue injury during the AKI process, and a variety of pro-inflammatory cytokines and chemokines are produced to drive the inflammatory response [ 41 ]. MCP-1 is a key chemokine in the inflammatory response, chemotactically directing inflammatory cells to the damaged kidney [ 42 ]. Immunohistochemical staining revealed that the MNPC@SC group had a notably reduced abundance of MCP-1-positive cells compared to the groups treated with MNP or MNPC ( Fig. 6 A). Additionally, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin1β (IL-1β), and interleukin-6 (IL-6) were detected using an enzyme-linked immunosorbent test ( Fig. 6 B–D). As expected, the levels of these pro-inflammatory cytokines were significantly increased in the AKI group, whereas the MNPC@SC group displayed the lowest levels. Myeloperoxidase (MPO), a lysosomal protein found in neutrophils, is a reliable biomarker for evaluating inflammation [ 43 ]. As demonstrated in Fig. 6 E, the increased level of MPO in the AKI group indicated that large neutrophils entered the renal lesion, triggering an injury response. Notably, the MNPC@SC group exhibited the most substantial suppression of MPO activity. Accordingly, immunofluorescent examination of the neutrophil-related Ly6G marker revealed consistent results, with the MNPC@SC group exhibiting considerably lower Ly6G expression than the other treatment groups ( Fig. 6 F). These results collectively provide compelling evidence that MNPC@SC can effectively suppress the infiltration of inflammatory cells and the release of inflammatory cytokines, with excellent anti-inflammatory properties to alleviate AKI. Fig. 6. Open in a new tab The anti-inflammatory effects of MNPC@SC in the AKI mice model. (A) Representative staining images of MCP-1 in each group. Scale bar = 100 μm. (B) TNF-α, (C) IL-6, and (D) IL-1β levels in renal tissues. Representative immunofluorescent staining images of (E) MPO and (F) Ly6G in the renal sections. Scale bar = 100 μm. Data are expressed as the mean ± SD (n = 3). ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001. Subsequently, to further investigate the protective mechanism of MNPC@SC, the levels of ROS and oxidation stress-related markers were analyzed. As shown in Fig. 7 A, DHE staining exhibited the excessive ROS generation in the AKI group, suggestive of AKI-induced oxidative stress. In contrast, the fluorescence signal was dramatically inhibited after the MNPC@SC treatment, which suggested that MNPC@SC could scavenge excessive ROS and reduce oxidative damage. MDA, an important indicator of oxidative stress, was employed to detect the level of ROS generated during lipid peroxidation. The MDA level in the AKI group was nearly three times higher than that in the control group ( Fig. 7 B). Notably, MDA levels dropped significantly in all treatment groups, with the MNPC@SC group witnessing the greatest decrease. Additionally, anti-oxidant enzymes like SOD and CAT play a critical role in maintaining cellular redox balance [ 44 ]. We further found that the levels of SOD and CAT were almost restored to normal levels in the MNPC@SC group, indicating the restoration of anti-oxidant capacity ( Fig. 7 C–D). Therefore, MNPC@SC effectively functions as a renoprotector by reducing oxidative stress-associated damage to the kidney, which could be attributed to the PA imaging-guided targeted therapy of MNPC@SC in AKI. Fig. 7. Open in a new tab The anti-oxidant effects of MNPC@SC in the AKI mice model. (A) The changes in renal ROS levels of mice after different treatments. Scale bar = 100 μm. (B) MDA, (C) SOD, and (D) CAT activities of kidney tissues in each group. Data are expressed as the mean ± SD (n = 3). ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001. 3.6. Safety assessment of MNPC@SC in mice Finally, we evaluated the biosafety of MNPC@SC, which was essential for biomedical applications. Initially, a hemolysis experiment of MNPC@SC was performed. The hemolysis rate of MNPC@SC was less than 10% even at high-dose (6.4 mg/mL), confirming their good biocompatibility in vitro ( Fig. 8 A). Furthermore, 24 h and 72 h after receiving the high-dose MNPC@SC injection, the mice were euthanized for blood routine and blood biochemical testing ( Fig. 8 B). The MNPC@SC group and the control group displayed no significant differences in blood routine or major liver and kidney function indicators. Additionally, the lack of apparent injury to major organs such as the heart, liver, spleen, lung, and kidney indicated that the MNPC@SC was biosafe in vivo ( Fig. 8 C). Taken together, these findings reveal that the MNPC@SC is a safe remedy for AKI protection. Fig. 8. Open in a new tab The biosafety of MNPC@SC. (A) Hemolysis analysis of MNPC@SC at different concentrations. (B) Blood routine and blood biochemical results of mice in each group. (C) Representative HE staining images of major organs of mice treated with saline and MNPC@SC. Scale bar = 100 μm. Data are expressed as the mean ± SD (n = 3). 4. Conclusion In conclusion, we have developed a unique pH-responsive kidney-targeting nanoplatform MNPC@SC to successfully accomplish precisely PA imaging-guided synergistic anti-oxidant, anti-apoptotic, and anti-inflammatory therapy for severe AKI. The MNPC@SC exhibited excellent biocompatibility by utilizing natural active ingredients Cur and MNPs. In the acidic pH condition of AKI, the MNPC@SC experienced responsive degradation, leading to the controllable release of therapeutic agents. The released MNPs could specifically illuminate the affected kidney to realize the self-monitoring of the MNPC@SC nanoplatform. We comprehensively evaluated the therapeutic effect of MNPC@SC in vivo and in vitro , unraveling its protective mechanism related to the inhibition of oxidative stress and inflammatory damage. Taken together, this responsive kidney-targeting nanoplatform, MNPC@SC, as a new natural remedy, achieves efficient PA imaging-guided three-in-one synergistic therapy for severe AKI. CRediT authorship contribution statement Xuhui Zhao: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Software, Writing – original draft. Yarong Jin: Conceptualization, Data curation, Formal analysis, Investigation, Software, Writing – original draft. Yahong Han: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft. Jin Zhang: Data curation, Investigation, Methodology, Visualization, Writing – review & editing. Qi Zhang: Conceptualization, Formal analysis, Software, Writing – original draft. Shilei Ren: Data curation, Formal analysis, Investigation, Methodology, Visualization. Juan Li: Data curation, Investigation, Software. Shijie Liu: Conceptualization, Data curation, Investigation. Jie Dong: Formal analysis, Methodology, Software. Jingmiao Wu: Investigation, Methodology, Software. Xiaojing Fu: Data curation, Investigation, Software. Ting Xu: Conceptualization, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. Jinghua Sun: Conceptualization, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. Ruiping Zhang: Conceptualization, Funding acquisition, Resources, Supervision, Validation, Visualization, Writing – review & editing. Declaration of competing interest The authors declare no conflict of interest in this work. Acknowledgements This work has been financially supported by the National Natural Science Foundation of China (82302279, U24A6012, 82120108016), the National Key R&D Program of China (2023YFC3402800), the National Ten Thousand Talents Program (SQ2022RA2A300118), Fundamental Research Program of Shanxi Province (202203021222369, 202403021212272, 202503021212371), Key Laboratory of Nano-imaging and Drug-loaded Preparation of Shanxi Province (202104010910010), Key R&D Program of Shanxi Province (202302130501015), the Health Commission of Shanxi Province (2025YD016), the Scientific and Technologial Innovation Programs of Higher Education Institutions in Shanxi (No.2024L180), the Science Fundation of Shanxi Health Commission (No.2025QM001), the China Postdoctoral Science Foundation Grant (2025M772198). Footnotes Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.mtbio.2026.103068 . Contributor Information Ting Xu, Email: [email protected]. 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