Hollow copper sulfide nanomedicines functionalized with metal polyphenol network for self-augmenting chemodynamic and photothermal therapy

Development of a self-augmenting CDT nanosystem overcomes Fenton reaction bottlenecks. • Cascade reaction amplifies H₂O₂ & Fe 3 ⁺ fuels and accelerates Fe 3 ⁺/Fe 2 ⁺ cycling. • pH/NIR-responsive gatekeeper ensures tumor-specific drug delivery. • Synergistic CDT/ PTT achieve highly potent antitumor efficacy. Chemodynamic therapy (CDT) holds promise for tumor treatment but is limited by insufficient endogenous hydrogen peroxide (H₂O₂) and slow Fe 3 ⁺/Fe 2 ⁺ cycling in the tumor microenvironment (TME). Herein, we report a self-augmenting nanoplatform (CPT@HCuS-TF) by loading camptothecin (CPT) into hollow copper sulfide (HCuS) nanoparticles and sealing with an Fe 3 ⁺-containing polyphenol network (MPN). Under acidic TME and near-infrared (NIR) irradiation, the MPN shell degrades to release Fe 3 ⁺, CPT is liberated to amplify endogenous H₂O₂ levels, and HCuS acts as a catalyst to accelerate the reduction of Fe 3 ⁺ to Fe 2 ⁺, thereby overcoming the rate-limiting step of the Fenton reaction and boosting hydroxyl radical (•OH) generation. Meanwhile, HCuS-mediated photothermal therapy (PTT) further enhances CDT efficacy. This synergistic strategy integrates self-supplied H₂O₂, accelerated iron redox cycling, and photothermal effects, achieving efficient antitumor activity in both in vitro and in vivo model, offering a robust paradigm for self-enhancing CDT-based combination therapy.