Tumor-specific peroxynitrite nanogenerator remodel physical barriers and abnormal metabolism in tumor to promote immunotherapy

The dense physical barrier of tumors and abnormal metabolism hinders the infiltration of T cells into the tumor microenvironment (TME) and weakens the efficacy of T-cell-mediated immunotherapy, such as immune checkpoint blockade (ICB) therapy. Herein, we specifically designed a pH-responsive peroxynitrite (ONOO⁻) nanogenerator (aPP-ArgNP^Fe, 127 ± 5 nm) based on an ArgNP and iron-phenolic-antibody (aPDL1) network to remodel the physical barriers and abnormal metabolism within the TME to enhance ICB immunotherapy. The aPP-ArgNP^Fe with PDL1 blocking ability to restore the effector function of T cells in TME. Upon cellular entry, the aPP-ArgNP^Fe structure disassembles completely (12 ± 5 nm) and leverages an iron-phenolic network and Arg to achieve sustained ONOO⁻ generation via •OH/NO cascade reactions. Notably, aPP-ArgNP^Fe degrades collagen in the tumor extracellular matrix, thereby increasing T cell infiltration in the TME. Besides, aPP-ArgNP^Fe effectively inhibits lactic acid production at the tumor site, benefiting from restoring abnormal metabolism. Significantly, aPP-ArgNP^Fe-mediated immunotherapy effectively reverses the immunosuppressive TME, evoking potent antitumor immune responses, including the restoration of CD8⁺IFN-γ⁺ T cell and M1-like macrophages infiltration, as well as the reduction of T regulatory cells and myeloid-derived suppressor cells. This study provides a novel strategy for enhancing the sensitivity of immunotherapy.