Photodynamically Sensitized Mitochondrial-Damage Amplification Strategy Promotes Pyroptosis-Induced Immunotherapy of Osteosarcoma.

The heterogeneity of osteosarcoma (OS) is the main reason for ineffective treatment and uncontrolled disease. Immunotherapy provides an ideal strategy to overcome the heterogeneity of OS, but effective activation of tumor-intrinsic immunogenicity remains challenging. We developed a biomimetic nanoplatform utilizing mitochondrial damage as a potent immunogenic trigger by employing the mitochondria-targeting compound cinnamaldehyde (CA) derived from traditional Chinese medicine. OS cell membrane-coated hollow MnO2 nanoparticles were used to deliver CA and chlorin e6. After accumulating at the tumor site and being internalized by tumor cells, CA release induces mitochondrial oxidative damage and produces hydrogen peroxide in combination with hollow manganese dioxide to alleviate the hypoxic microenvironment. Finally, a mitochondrial-damage amplification mechanism is formed to trigger tumor pyroptosis under the synergy of adjustable photodynamic therapy. Released damage-associated molecule patterns and damaged double-stranded DNA inside tumor cells promote dendritic cell maturation by activating the cGAS-STING (cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) signaling axis. Through CA-triggered amplification of mitochondrial damage, dual immunogenic pathways reshape the immunosuppressive microenvironment, overcoming OS heterogeneity and inhibiting distal metastasis. This strategy provides new opportunities for tumor-intrinsic immunogenic activation.