A comprehensive immune cycle enhancement strategy for alternative splicing-mediated endogenous Tumor neoantigens generation and delivery.

Although immunotherapy exhibits remarkable clinical potential for the treatment of tumors, immune responses generated by conventional approaches often fail to completely eradicate osteosarcoma. This inadequacy stems primarily from the low immunogenicity of osteosarcoma-derived neoantigens and the limitations of conventional strategies that focus on enhancing only a single step in the tumor immunity cycle and fail to effectively drive a comprehensive immune response. To address these challenges and augment antitumor immune responses, we developed the innovative core-shell nanoparticle system BaTiO3-indisulam@PD1-cell Membrane Nanoparticles (BI@PCM NPs). This system achieves tumor targeting and enables the ultrasound-triggered controlled release of components. Unlike traditional methods that rely on DNA damage-mediated neoantigen production, BI@PCM disrupts alternative RNA splicing, thereby generating high-quality Endogenous Tumor Neoantigens (ETNs). These ETNs are dynamically transported from the tumor site to lymph nodes (LNs) using BaTiO nanocubes (≈10 nm) as efficient nanocarriers. BaTiO acts as a piezoelectric catalyst, producing reactive oxygen species (ROS) upon ultrasound stimulation, further enhancing the immunogenic death of osteosarcoma cells. Integration of Pd1 cell membrane coating provides enhanced targeting capabilities and significantly amplifies cytotoxic T-cell activation. By strengthening multiple immune cycle steps, BI@PCM exhibits immense potential to revolutionize personalized tumor immunotherapy and provide a robust solution for osteosarcoma treatment.