Mn3O4 Nanoshell Coated Metal–Organic Frameworks with Microenvironment‐Driven O2 Production and GSH Exhaustion Ability for Enhanced Chemodynamic and Photodynamic Cancer Therapies

Abstract Nanomedicine exhibits emerging potentials to deliver advanced therapeutic strategies in the fight against triple‐negative breast cancer (TNBC). Nevertheless, it is still difficult to develop a precise codelivery system that integrates highly effective photosensitizers, low toxicity, and hydrophobicity. In this study, PCN‐224 is selected as the carrier to enable effective cancer therapy through light‐activated reactive oxygen species (ROS) formation, and the PCN‐224@Mn 3 O 4 @HA is created in a simple one‐step process by coating Mn 3 O 4 nanoshells on the PCN‐224 template, which can then be used as an “ROS activator” to exert catalase‐ and glutathione peroxidase‐like activities to alleviate tumor hypoxia while reducing tumor reducibility, leading to improved photodynamic therapeutic (PDT) effect of PCN‐224. Meanwhile, Mn 2+ produced cytotoxic hydroxyl radicals (∙OH) via the Fenton‐like reaction, thus producing a promising spontaneous chemodynamic therapeutic (CDT) effect. Importantly, by remodeling the tumor microenvironment (TME), Mn 3 O 4 nanoshells downregulated hypoxia‐inducible factor 1 α expression, inhibiting tumor growth and preventing tumor revival. Thus, the developed nanoshells, via light‐controlled ROS formation and multimodality imaging abilities, can effectively inhibit tumor proliferation through synergistic PDT/CDT, and prevent tumor resurgence by remodeling TME.