Hyaluronic acid-targeted copper/manganese nanobioreactor with H2O2 self-supply for simultaneous induction of ferroptosis and apoptosis in hepatocellular carcinoma.

While doxorubicin (DOX)-based chemotherapy have revolutionized cancer treatment, their clinical potential is limited by off-target toxicity and low delivery efficiency. Reactive oxygen species (ROS)-based dynamic therapy has emerged as a cutting-edge modality for tumor-specific treatment. Herein, we introduce a tumor-microenvironment-activited Cu/Mn-based nanoreactor (CuO2@PMDH) that integrates targeted DOX delivery with chemodynamic therapy (CDT). The nanoreactor features CuO2 encapsulated in a hyaluronan-modified Mn-based complex as the dominant component, enabling sequential activation by elevated glutathione (GSH) and H2O2 in the tumor microenvironment. Within tumor cells, degradation of the nanoreactor co-releases DOX and CuO2, and subsequent acid-triggered hydrolysis of CuO2 provides more H2O2 locally that fuels a Cu/Mn-mediated Fenton-like reaction, generating highly toxic hydroxyl radicals (·OH). This amplified oxidative stress significantly triggers ferroptosis-an iron-independent form of regulated cell death driven by lipid peroxidation-thereby achieving a potent synergistic antitumor effect. In murine models, Cu/Mn nanoreactors showed potent antitumor efficacy through DOX-targeted delivery and efficient oxidative damage to tumor tissues. This spatiotemporally controlled dual-release strategy minimizes systemic toxicity while synergizing CT and CDT, offering a promising strategy for targeted cancer therapy.