Manganese-potentiated cGAS–STING activation with ATM/PRMT5 inhibition remodels the immunosuppressive microenvironment in osteosarcoma via bone-targeted delivery

Osteosarcoma (OS), the most common malignant bone tumor, remains challenging to treat because of poor drug delivery to bone tissue and limited response to immunotherapy. To overcome these hurdles, we developed a bone-targeted, glutathione (GSH)-responsive polymeric nanoparticle (NP ALN/Mn -AP) that chelates manganese (Mn) and delivers an ATM inhibitor (AZD0156) and a PRMT5 inhibitor (GSK3326595). By functionalizing this nanoplatform with alendronate (ALN) into NP ALN/Mn -AP, we achieve preferential accumulation in bone tumors. Upon cellular uptake, elevated intracellular GSH levels in OS cells trigger the controlled release of both inhibitors. Inhibiting ATM and PRMT5 amplifies DNA damage and activates the cGAS-STING pathway, while Mn ions further enhance this innate immune signaling by promoting cytosolic DNA sensing. Together, these effects reshape the tumor microenvironment toward a more immune-responsive state and promote antitumor immunity in osteosarcoma. In vivo studies demonstrate that NP ALN/Mn -AP significantly inhibits OS progression and boosts systemic immune responses. This dual-action, bone-specific nanotherapeutic platform synchronized DNA-repair inhibition and Mn-enhanced immune-stimulation, offering a promising new approach for effective osteosarcoma treatment. • Bone-targeted, GSH-responsive NP ALN/Mn -AP co-delivers ATM/PRMT5 inhibitors and Mn²⁺ for combined OS therapy. • Dual ATM/PRMT5 inhibition triggers cytosolic DNA accumulation and activates cGAS–STING signaling in OS. • Released Mn²⁺ further boosts STING signaling and amplifies innate immune activation in the tumor microenvironment. • NP ALN/Mn -AP remodels the immunosuppressive microenvironment, increases T-cell infiltration, and improves PD-1 response. Together, these findings establish a mechanism-driven therapeutic strategy that integrates DDR inhibition with cGAS–STING amplification to improve immunotherapy responsiveness in osteosarcoma.