Protein Corona-Tailored Nanoplatform Boosts Tumor Accumulation and Reprograms Macrophages for Osteosarcoma Therapy

Osteosarcoma is featured with an immunosuppressive tumor microenvironment (TME) and limited therapeutic efficacy. Herein, we report a pH-responsive nanoplatform based on calcium phosphate (CaP)-coated Prussian blue nanoparticles (PB@CaP NPs) for optimized systemic delivery and antitumor immune response. The CaP interface inhibits the protein corona formation in blood, reducing complement-mediated clearance and prolonging circulation, and enhancing tumor accumulation of the nanoparticles. The pH-responsive dissolution of PB@CaP NPs enables the sequential release of calcium ions in the acidic TME and iron ions in lysosomes, together with the peroxidase-like catalytic activity of the PB core, establishing a synergistic ion/nanozyme signaling axis that triggers robust ROS generation and oxidative stress, thereby reprogramming tumor-associated macrophages from an immunosuppressive M2-like to a pro-inflammatory M1-like phenotype and remodeling the tumor immune microenvironment. This study provides a rational surface engineering strategy for nanoimmunotherapy.