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

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.