Surface-Charge-Switchable Nanoclusters for Magnetic Resonance Imaging-Guided and Glutathione Depletion-Enhanced Photodynamic Therapy

[Image: see text] Photodynamic therapy (PDT) is an effective noninvasive therapeutic method that employs photosensitizers (PSs) converting oxygen to highly cytotoxic singlet oxygen ((1)O(2)) under light irradiation. The conventional PDT efficacy is, however, compromised by the nonspecific delivery of PSs to tumor tissue, the hypoxic tumor microenvironment, and the reduction of generated (1)O(2) by the intracellular antioxidant glutathione (GSH). Herein, an intelligent multifunctional synergistic nanoplatform (CMGCC) for T(1)-weighted magnetic resonance (MR) imaging-guided enhanced PDT is presented, which consists of nanoparticles composed of catalase (CAT) and manganese dioxide (MnO(2)) that are integrated within chlorin-e6-modified glycol chitosan (GC) polymeric micelles. In this system, (1) GC polymers with pH-sensitive surface charge switchability from neutral to positive could improve the PS accumulation within the tumor region, (2) CAT could effectively reoxygenate the hypoxic tumor via catalyzing endogenous hydrogen peroxide to O(2), and (3) MnO(2) could consume the intracellular GSH while simultaneously producing Mn(2+) as a contrast agent for T(1)-weighted MR imaging. The CMGCC particles possess uniform size distribution, well-defined structure, favorable enzyme activity, and superior (1)O(2) generation ability. Both in vitro and in vivo experiments demonstrate that the CMGCC exhibit significantly enhanced PDT efficacy toward HeLa cells and subcutaneous HeLa tumors. Our study thereby demonstrates this to be a promising synergistic theranostic nanoplatform with highly efficient PDT performance for cancer therapy.