Oxidation-activated nanotherapy boosts tumor immunity and disrupts tumor-nerve crosstalk to combat bone metastases and cancer pain.

Bone metastasis remains a formidable challenge in oncology due to the interdependent triad of immunosuppression, neuropathic pain, and osteolytic destruction. Current treatments fail to holistically address these pathophysiological axes. Here, we develop a reactive oxygen species (ROS)-responsive liposomal nanoplatform (LipoNCs@pGSDMB) that codelivers a polymeric stimulator of interferon genes (STING) agonist and a gasdermin B (GSDMB) plasmid for dual neuro-immune modulation. Upon tumor-selective activation in metastatic bone niches, this nanotherapy induces STING-driven immune priming and GSDMB-mediated pyroptosis, triggering potent antitumor responses. Crucially, LipoNCs@pGSDMB restore voltage-gated calcium channel (VGCC) expression in tumor cells, a prognostic biomarker identified through multiomics analysis of clinical specimens, thereby blocking calcium-dependent neurosignaling and disrupting prometastatic tumor-nerve cross-talk. In breast cancer bone metastasis models, this approach achieves 94% tumor suppression, complete pain resolution, and efficient bone restoration. By converging oxidation-responsive nanomaterial engineering, immunomodulation, and neural circuit reprogramming, this work establishes a paradigm-shifting neuroimmunotherapy platform that dismantles the self-reinforcing metastasis niche while addressing its debilitating sequelae.