Lactolytic and TGFβ-inhibiting nanoplatform overcomes immunosuppression to enhance radiosensitivity in osteosarcoma

Osteosarcoma, the most prevalent malignant bone tumor in adolescents, presents significant clinical challenges due to its aggressive nature and resistance to conventional therapies including radiotherapy. Through analysis of human osteosarcoma specimens, we identified lactate and TGFβ as key regulators of the tumor microenvironment (TME), which collectively induce an immunosuppressive osteosarcoma microenvironment. To address this, we developed a novel multifunctional nanosystem constructed by genetically engineering lactate oxidase (LOX)-anchored platelet membranes to encapsulate manganese dioxide (MnO 2 ) nanoparticles and the TGFβ inhibitor SB525334. This system demonstrates tumor-selective accumulation while simultaneously enabling lactate catabolism and TGFβ suppression. In vitro and in vivo studies confirmed that this synergistic approach effectively inhibits TGFβ-mediated signaling pathways and enhances T cell-mediated anti-tumor immunity. Furthermore, combination therapy with PD-L1 blockade significantly suppressed tumor growth and reduced recurrence rates, demonstrating robust adaptive immune responses. These findings highlight the transformative potential of engineered platelet membrane nanosystems in integrating metabolic modulation with immune regulation to improve current osteosarcoma treatment paradigms. • Dual-targeting LP@MT nanoplatform delivers LOX and MnO₂/SB525334 to tumors for lactate breakdown and TGFβ blockade. • LOX-MnO₂ cascade depletes lactate, generates O₂, reverses hypoxia, and reprograms T-cell metabolism to boost CTLs and suppress Tregs. • With PD-L1 blockade, LP@MT enhances radiosensitization, drives tumor regression, and reduces recurrence in vivo and in organoids.