Domain-Confined Nano-Transformers Enable Efficient In Situ Peroxynitrite Generation for Potentiated Tumor Immunotherapy.

Activating the tumor immune response via reactive nitrogen species (RNS) holds promise for advancing tumor immunotherapy. However, current strategies fail to achieve sufficient local RNS concentrations due to the inefficiency of in situ generation within tumor cells. Here, we report the rational design of conformation-switching, domain-confined nanotransformers (CaO2-Arg) that enable efficient on-site peroxynitrite (ONOO-) production by orchestrating spatially restricted bimolecular collisions between reactive oxygen species (ROS) and nitric oxide (NO) precursors. Upon exposure to the acidic tumor microenvironment, the nanotransformers undergo disassembly and reassembly, resulting in the controlled release of H2O2 and NO, and subsequent formation of ONOO- in situ. This spatial confinement dramatically enhances reaction efficiency, leading to potent tumor cytotoxicity and robust induction of immunogenic cell death (ICD). This domain-confined, conformation-switching nanoplatform provides a promising strategy for next-generation RNS-based tumor immunotherapy.