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

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@Mn3O4@HA is created in a simple one-step process by coating Mn3O4 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, Mn2+ produced cytotoxic hydroxyl radicals (center dot OH) via the Fenton-like reaction, thus producing a promising spontaneous chemodynamic therapeutic (CDT) effect. Importantly, by remodeling the tumor microenvironment (TME), Mn3O4 nanoshells downregulated hypoxia-inducible factor 1 alpha 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.