M1 macrophage-derived fusogenic nanovesicles co-loaded with Fe3O4/IR780 suppress osteosarcoma via a sonodynamic-ferroptosis-immune triad

Osteosarcoma, a highly aggressive and metastatic bone malignancy, remains difficult to treat with current therapeutic modalities, leading to unsatisfactory clinical outcomes. Emerging evidence indicates that ferroptosis induction and antitumor immune activation represent promising therapeutic avenues. Herein, we engineer a biomimetic nanoplatform, termed IR780@NVEV-Fe3O4 (IFV), by fusing M1 macrophage-derived extracellular vesicles with extruded nanovesicles preloaded with Fe3O4 nanoparticles and the sonosensitizer IR780, aiming to integrate sonodynamic therapy (SDT), ferroptosis induction, and immunotherapy into a single system. The IFV nanoplatform exhibits excellent tumor-targeting capability and pronounced ultrasound responsiveness. In vitro, ultrasound-activated IFV potently induces ferroptosis in osteosarcoma cells, as evidenced by enhanced lipid peroxidation, mitochondrial dysfunction, and suppression of the GPX4/xCT axis. Notably, this process concurrently triggers immunogenic cell death (ICD), thereby promoting dendritic cell maturation and macrophage polarization toward the M1 phenotype. In murine osteosarcoma models, IFV combined with ultrasound markedly inhibits subcutaneous tumor growth and pulmonary metastasis. Importantly, the combination of IFV-mediated sonodynamic therapy with anti-PD-L1 antibody elicits a robust systemic antitumor immune response, characterized by enhanced intratumoral CD8⁺ T cell infiltration, establishment of long-term immunological memory, and a substantial prolongation of host survival. Collectively, this study presents a versatile biomimetic nanoplatform that operates through a self-reinforcing “sonodynamic-ferroptosis- immune” triad, providing a promising and effective combinatorial strategy for osteosarcoma therapy.