Biomimetic polymeric nanoreactors with photooxidation-initiated therapies and reinvigoration of antigen-dependent and antigen-free immunity

Abstract

Immune cell-mediated anticancer modalities usually suffer from immune cell exhaustion and limited efficacy in solid tumors. Herein, the oxygen-carrying biomimetic nanoreactors (BNR2(O₂)) have been developed with photooxidation-driven therapies and antigen-dependent/antigen-free immune reinvigoration against xenograft tumors. The BNR2(O₂) composes polymeric nanoreactors camouflaged with cancer cell membranes can efficiently target homotypic tumors. It continuously releases O₂ to boost intracellular reactive oxygen species (ROS) to oxide diselenide bonds, which controllably releases seleninic acids and anti-folate Pemetrexed compared to hydrogen peroxide and glutathione incubation. The O₂-rich microenvironment sensitizes Pemetrexed and blocks programmed cell-death ligand 1 (PD-L1) to reverse T cell immunosuppression. The ROS and Pemetrexed upregulate pro-apoptosis proteins and inhibit folate-related enzymes, which cause significant apoptosis and immunogenic cell death to stimulate dendritic cell maturation for improved secretion of cytokines, expanding antigen-dependent T cell immunity. Furthermore, by regulating the release of seleninic acids, the checkpoint receptor human leukocyte antigen E of tumor cells can be blocked to reinvigorate antigen-free natural killer cell immunity. This work offers an advanced antitumor strategy by bridging biomimetic nanoreactors and modulation of multiple immune cells.