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. 2025 Aug 23;23(1):584.
doi: 10.1186/s12951-025-03626-1.

Nanoengineered hydrogels disrupt tumor antioxidant defense via photothermal-chemodynamic synergy and oxidative stress boosts

Leiguang Ye  1 , Yang Qiao #  2 , Peisan Wang #  2 , Wei Li  3 , Xianwen Wang  4 , Yiqun Zhang  5 , Zhennan Yuan  6
Affiliations

Nanoengineered hydrogels disrupt tumor antioxidant defense via photothermal-chemodynamic synergy and oxidative stress boosts

Leiguang Ye et al. J Nanobiotechnology. .

Abstract

By integrating photothermal and chemodynamic properties, Ru-based nanomaterials have emerged as promising agents for tumor therapy. However, their clinical translation is hindered by high systemic toxicity, suboptimal therapeutic efficacy, and compromised chemodynamic performance caused by tumor antioxidant defense mechanisms. A multifunctional therapeutic platform (Ru-PC-PEITC-ALG) was developed through the coordination-driven self-assembly of ruthenium ions with procyanidins (PCs) to form Ru-PC nanoparticles, followed by coencapsulation with phenethyl isothiocyanate (PEITC) in a sodium alginate hydrogel. The Ru-PC complex demonstrated exceptional photothermal conversion efficiency, enabling rapid intratumoral temperature elevation under 808 nm laser irradiation to achieve localized thermal ablation. Simultaneously, Ru-PC exhibited tumor microenvironment-responsive catalytic activity, catalyzing the conversion of hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH) via Fenton-like reactions. This ROS generation was substantially amplified through synergistic photothermal acceleration of reaction kinetics and PEITC-mediated glutathione (GSH) depletion, which effectively disabled the antioxidant defense system. Systematic evaluations, including in vitro cytotoxicity assays, transcriptomic sequencing, and murine xenograft models, confirmed the platform's superior tumor suppression ability and favorable biosafety profile. Mechanistic studies revealed that combination therapy induced mitochondrial dysfunction and activated the apoptosis/ferroptosis pathways. This work presents a "precision disruption" strategy against tumor antioxidant armor, advancing the rational design of metal‒polyphenol-coordinated nanomaterials for enhanced oncotherapy.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The animal studies have been approved by the Ethics Committee of Anhui Medical University (No. LLSC20220731) and all handling of mice was performed in accordance with the institutional regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Characterization of Ru-PC. (a-b) High-resolution TEM images of Ru-PC. (c) EDS energy spectra of Ru-PC. (d) TEM elemental mapping images of Ru-PC. (e-g) Energy spectra of Ru-PC detected by XPS
Fig. 2
Fig. 2
Multiple enzyme activities of Ru-PC and the biological activity of PEITC. (a) Schematic diagram of multiple enzyme activity assays for Ru-PC and PEITC. (b-c) Changes in the TMB absorbance curves after treatment with different concentrations of Ru-PC or H2O2. (d-e) Changes in OPD absorbance curves after treatment with different concentrations of Ru-PC or H2O2. (f) Changes in the absorbance curves of DTNB with time after the reaction of 200 µg/mL Ru-PC with GSH. (g) Rate of GSH consumption by different concentrations of Ru-PC. (h) Changes in the color development of DNTB after the reaction of GSH with 1 µmol/L PEITC
Fig. 3
Fig. 3
Characterization and photothermal properties of Ru-PC-PEITC-ALG. (a) SEM images of Ru-PC-PEITC-ALG. (b-e) Rheological properties, including rheological viscosity, viscoelasticity, linear viscoelastic region, structural damage and recovery properties, of Ru-PC-PEITC-ALG compared with those of ALG. (f) Release rates of Ru from Ru-PC and Ru-PC-PEITC-ALG over 72 h in a simulated TEM environment. (g-h) Infrared thermography images and (i-j) warming curves of Ru-PC-PEITC-ALG under 808 nm NIR irradiation at different concentrations and light intensities. (k) Stability curves of the PC-PEITC-ALG photothermal cycle
Fig. 4
Fig. 4
In vitro antitumor ability of Ru-PC-PEITC-ALG. (a-b) CCK-8 assay for the independent inhibition of 4T1 cell activity by different concentrations of Ru-PC and PEITC. (c) CCK-8 assay for determining the activity of 4T1 cells in different groups. The groupings of a-g are as follows: control; ALG + laser; Ru-PC-ALG; PEITC-ALG; Ru-PC-PEITC-ALG; Ru-PC-ALG + laser; and Ru-PC-PEITC-ALG + laser. (d) CLSM images of different groups of live‒dead cells. (e) Flow cytometric analysis of different subgroups of apoptotic cells
Fig. 5
Fig. 5
Antitumor mechanism of Ru-PC-PEITC-ALG. (a) ROS fluorescence staining (DCFH-DA) CLSM image. (b) Mitochondrial membrane potential (JC-1) CLSM image. (c) CLSM image of intracellular GSH staining. (d) Semiquantitative analysis of ROS fluorescence staining and fluorescence. The groupings of a-g are as follows: control; ALG + laser; Ru-PC-ALG; Ru-PC-ALG + laser; PEITC-ALG; Ru-PC-PEITC-ALG; and Ru-PC-PEITC-ALG + laser. (e) Fluorescence semiquantitative analysis of intracellular GSH staining
Fig. 6
Fig. 6
Transcriptome sequencing. (a) Schematic diagram of the molecular mechanism of Ru-PC-PEITC-ALG intracellular antitumor therapy. (b) Heatmap of DEGs in the treatment and control groups. (c) Volcano plot of the DEGs. (d) GSEA enrichment analysis of DEGs. (e) Top 30 results of the KEGG enrichment analysis. (f) Top 30 terms from the GO enrichment analysis
Fig. 7
Fig. 7
In vitro antitumor properties of Ru-PC-PEITC-ALG. (a) Schematic of the animal model construction and treatment. (b) Curve of body weight changes in each animal subgroup during treatment. (c) Digital photographs of isolated tumor tissues. (d-e) Tumor volume curves during treatment for each subgroup. (f) Micrographs of H&E, Ki67, TUNEL, ROS and Caspase 3 staining of tumor tissue sections from each subgroup
Fig. 8
Fig. 8
Ru-PC-PEITC-ALG biosafety. (a) Changes in routine blood and blood biochemical indices in animals within 14 days after the injection of Ru-PC-PEITC-ALG. (b) H&E staining images of major organs within 14 days after Ru-PC-PEITC-ALG injection
Fig. 9
Fig. 9
Schematic representation of the synthesis and antitumor mechanism of Ru-PC-PEITC-ALG. (a) Synthesis process of Ru-PC. (b) Synthesis flow of Ru-PC-PEITC-ALG. (c-d) Process and molecular biological mechanism of the intracellular antitumor effect of Ru-PC-PEITC-ALG
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