Co‐Delivery of Cisplatin and Curcumin via ROS‐Responsive Nanoparticles to Activate the cGAS‐STING Pathway for Osteosarcoma Metalloimmunotherapy

Cisplatin (Cis) is widely recognized as the cornerstone of osteosarcoma (OS) chemotherapy. However, its clinical effectiveness remains limited by poor drug delivery efficiency, severe adverse effects, and emerging chemoresistance. To overcome these limitations, a triple-drug co-delivery system (NP3) is designed, encapsulating Cis prodrug (Cis(IV)), curcumin (Cur), and manganese ions within reactive oxygen species (ROS)-responsive nanoparticles (NPs). NP3 efficiently accumulated at tumor sites and rapidly released its therapeutic payload upon endocytosis, triggered by abundant intracellular ROS. After NP3 degradation, Cis in combination with Cur induced significant DNA damage. This DNA debris subsequently activated the cGAS-STING pathway, enhancing tumor immunogenicity. Additionally, manganese ions functioned as immune adjuvants, further amplifying cGAS-STING activation. Consequently, NP3 promoted dendritic cell (DC) maturation, enhanced the infiltration of CD8+ T-cells, and concurrently decreased the infiltration of immunosuppressive cells. In an OS mouse model, combining NP3 with anti-PD-L1 treatment markedly improved both tumor suppression and immune system activation. RNA sequencing analysis demonstrated that NP3 synergistically promoted tumor regression by concurrently inducing pro-apoptotic signaling and immune responses. In conclusion, this study presents an innovative therapeutic strategy combining targeted chemotherapy delivery with robust antitumor metalloimmunotherapy, offering a promising therapeutic approach for OS.