Activation of pyroptosis and immunogenic cell death by targeted liposomal cisplatin for enhanced chemo-immunotherapy for osteosarcoma

Abstract

Low delivery efficiency and accompanying systematic toxicity of therapeutic agents have affected the efficacy of chemotherapy for osteosarcoma (OS). Meanwhile, the chemotherapy based on cisplatin, as the single modality, has reached the limits. Here, we designed a liposome nanotheranostic platform that combined cisplatin with decitabine to simultaneously activate the pyroptosis and immunogenic cell death in an effective delivery manner. Specifically, we prepared the targeted liposomal therapeutics (NPCD@ALN). NPCD@ALN effectively accumulated at the bone lesion induced by OS in vivo. Meanwhile, NPCD@ALN released NPCD and ALN when reaching the acidic tumor microenvironment, thus the charge reversing from negative to positive and enabling the better endocytosis of NPCD. NPCD activated caspase-3 to cleave GSDME into pore-forming GSDME-N terminal, letting the cancer cell release pro-inflammatory factors into the extracellular microenvironment. Subsequently, the released inflammatory cytokines promoted the maturation of antigen-presenting cells, the infiltration of cytotoxic T cells and the remodeling of immunosuppressive microenvironment. Eventually, NPCD triggered pyroptosis and immunogenic cell death and evoked the adaptive immune response to realize the powerful synergistic chemotherapy and immunotherapy for osteosarcoma. To summarize, this study exemplified rational therapeutics which facilitated the activation of pyroptosis and antitumor immune response by targeted liposomal cisplatin, and provided innovative combined-therapeutic strategies for osteosarcoma.