A Photosensitizer-Engineered Nanoplatform Exposed to NIR Laser for Mitochondria Targeting and Chemo/Photodynamic Synergistic Therapy against Glioma

Targeted mitochondrial-based therapeutic strategies for tumors have emerged as a significant research focus in the field of cancer treatment in recent years. Mitochondria, often referred to as the "energy factory" of cells, play a crucial role in the metabolic reprogramming of tumor cells, as well as in oxidative stress and immune evasion. In this study, we utilized a mitochondria-targeted photosensitizer, IR780, to engineer Celastrol (Cela)-loaded lipid nanoparticles, designed as Cela@Lip-IRH, for the synergistic therapy of chemotherapy and photodynamic therapy (PDT) against glioma. Cela@Lip-IRH could respond to the weakly alkaline environment of tumor cell mitochondria for rapid Cela release. Leveraging the mitochondrial targeting capacity and PDT property of IR780, Cela@Lip-IRH nanoparticles showed enhanced cellular uptake and mitochondria targeting distribution <i>in vitro</i>, as well as obvious tumor accumulation <i>in vivo</i>. Cela@Lip-IRH nanoparticles exhibited prominent intracellular reactive oxygen species (ROS) generation upon NIR laser irradiation, which was accompanied by pronounced photocytotoxicity and cell apoptosis, finally producing remarkable tumor growth suppression efficacy <i>in vivo</i>. We further verified that the potential antitumor molecular mechanism was triggered by the release of Cytochrome C, leading to an activated mitochondrial apoptosis pathway, alongside an immune response characterized by enhanced recruitment of CD4⁺ T cells and CD8⁺ T cells in tumor tissues. Currently, this mitochondria-targeted nanoplatform presents an ideal method to enhance the synergistic performance of chemotherapy and PDT in glioma, and it is anticipated that such a strategy will provide a promising alternative to optimize the tumor-targeted therapies.