A dual-function hyaluronic acid-encapsulated nanoplatform enables triple GSH depletion for apoptosis-ferroptosis synergistic oncotherapy.

Ferroptosis has emerged as an alternative strategy to eradicate apoptosis-resistant tumor cells. However, the hypoxia and redox homeostasis in tumor microenvironment (TME) hinder effective ferroptosis induction. Herein, we report a multifunctional MnO2-nanoclusters-decorated Cu2+-doped mussel-inspired mesoporous polydopamine (CM) nanoplatform, which is further engineered by co-loading sorafenib (SRF) and indocyanine green (ICG) with the help of a cargo-loading and targeting-capable hyaluronic acid (HA) shell to obtain CMMSIH. Once accumulating in tumors, the MnO2 nanoclusters catalyze glutathione (GSH) oxidation and H2O2 decomposition to deplete intracellular GSH and alleviate hypoxia. The released SRF and exposed CM core are further devoted to inhibiting de novo GSH synthesis and scavenging endogenous GSH, respectively. This triple-modal GSH depletion inactivates intracellular glutathione peroxidase 4 (GPX4), thereby amplifying the potential for ferroptosis. Besides, the Cu2+-mediated fenton-like reaction and ICG-based photodynamic process generate abundant reactive oxygen species (ROS), further amplified by photothermal effect and MnO2-supplied oxygen of CMMSIH. This design synergistically achieves GPX4 inactivation, hypoxia alleviation and ROS accumulation, thus disrupting intracellular redox homeostasis and ultimately triggering the ferroptotic and apoptotic death of tumor cells. In vivo studies demonstrate that CMMSIH nanoplatform inhibits tumor growth without systemic toxicity, offering a promising multimodal strategy to overcome the limitations of TME.