Ultrasound-responsive bone-targeting liposomes suppress osteosarcoma through enhanced ROS generation and immunogenic cell death.

Sonodynamic therapy (SDT) demonstrates significant therapeutic potential for deep-seated tumors such as osteosarcoma due to its non-invasive tissue penetration capability. Enhancing reactive oxygen species (ROS) generation efficiency and triggering endogenous immunoamplification pathways are key to improving SDT-mediated osteosarcoma suppression. This study proposes an SDT-based nano-immunoamplifier strategy. Specifically, DSPE-PEG derivatives are successfully grafted with phytic acid (PA) and the sonosensitizer indocyanine green (ICG) via esterification and amidation reactions. Subsequently, ultrasound-responsive bone-targeting nanoliposomes (LPIM) were constructed by co-assembling MnO₂ nanoparticles (3-5 nm) with DSPE-PEG derivatives using the thin-film hydration method. The LPIM achieves targeted delivery to osteosarcoma osteolytic regions through the phosphate groups of PA. The multimodal effects of MnO₂ alleviate the hypoxic tumor microenvironment and suppress the antioxidant barrier of reduced glutathione (GSH), thereby enhancing ROS generation efficiency and SDT-induced immunogenic cell death (ICD). Concurrently, the release of Mn2+ activates the cGAS-STING signaling pathway, triggering endogenous immunoamplification. LPIM achieves osteosarcoma targeting within 24 h in vivo, and under exogenous low-intensity focused ultrasound (US) activation, it markedly suppresses primary osteosarcoma growth (tumor inhibition rate: 93.5%), alleviates osteolysis and inhibits distant metastasis and pulmonary dissemination of osteosarcoma. Collectively, this nano-immunoamplifier strategy provides novel insights into SDT-based therapy for osteosarcoma.