MnO2-Incorporated Magnetic Nanoparticles with pH-Responsive Drug Release Enhance Hypoxia-Resistant Photodynamic Therapy for Melanoma

Background/Objectives: Photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment, which restricts reactive oxygen species (ROS) generation and compromises therapeutic efficacy. To address this critical barrier, we engineered a multifunctional nanocomposite (Pha@FSMP) integrating oxygen supplementation, pH-responsive drug release, and magnetic targeting for enhanced PDT. Methods: The platform is constructed with a superparamagnetic Fe3O4 core, coated in amino-functionalized mesoporous silica (mSiO2) loaded with MnO2 as an oxygen-evolving catalyst, and surface-conjugated with the pH-responsive copolymer PEG-b-PAsp to encapsulate the hydrophobic photosensitizer Pha. We characterized its core physicochemical and functional properties, and evaluated its photodynamic efficacy via in vitro cellular assays and in vivo studies in a murine melanoma model. Results: In vitro assays demonstrated significant elevation of intracellular ROS levels and enhanced PDT-mediated cytotoxicity against B16-F10 melanoma cells. In vivo studies in a murine melanoma model confirmed potent tumor growth inhibition, metastasis suppression, and prolonged survival, accompanied by excellent biosafety. Conclusions: Collectively, this oxygen-augmented nanocomposite represents a promising strategy to overcome hypoxia-associated PDT resistance, offering a translatable platform for improved cancer therapy.