Mitochondria-targeted photodynamic nanoparticles boost antitumor immunity by suppressing mitophagy in osteosarcoma

Osteosarcoma (OS) responds poorly to immunotherapy owing to its highly immunosuppressive phenotype. Photodynamic therapy (PDT) can induce mitochondrial damage by generating reactive oxygen species (ROS), thereby triggering immunogenic cell death (ICD) and activating antitumor immunity. However, mitochondrial damage readily activates mitophagy, which attenuates oxidative stress and compromises therapeutic efficacy. In this study, we construct a multifunctional nanoparticle (TPSM@IT-4Cl), which co-loads the photosensitizer IT-4Cl and the mitochondrial fission inhibitor Mdivi-1 and can target mitochondria. TPSM@IT-4Cl is selectively delivered to the mitochondria of tumor cells and releases drugs in a glutathione (GSH)-responsive manner within a high-GSH microenvironment. Under localized light irradiation, TPSM@IT-4Cl efficiently generates ROS via IT-4Cl to induce mitochondrial damage, while the released Mdivi-1 inhibits mitochondrial fission and thereby indirectly interferes with mitophagy, ultimately amplifying the efficacy of PDT. Both in vitro and in vivo studies indicated that the resulting ICD remodels the tumor immune microenvironment and elicits potent anti-tumor immunity. Moreover, TPSM@IT-4Cl exhibits significant antitumor efficacy in OS patient-derived xenograft (PDX) models, highlighting its translational potential. Collectively, we developed a mitochondria-targeted photodynamic nanoparticle with concomitant mitophagy inhibition, which may provide a feasible strategy to overcome the limitations of immunotherapy in OS.