Homologous-targeted and tumor microenvironment-activated hydroxyl radical nanogenerator for enhanced chemoimmunotherapy of non-small cell lung cancer

Abstract

Abstract Non-small cell lung cancer (NSCLC) has a low response rates to platinum-based chemotherapy represented by cisplatin (CDDP), and the combination regimen of CDDP and immune checkpoint blockers (ICBs) has demonstrated limited therapeutic efficacy and increased side effects in clinical trials. In this study, we prepare a cancer cell membrane camouflaged-nanocomplex that precisely delivers CDDP and programmed death-ligand 1 (PD-L1)-targeted antagonistic DNA aptamers (Apt) to the tumor, and responsively releases therapeutic cargos and ferrous ions (Fe2+) accompanying with the degradation under the acidic tumor microenvironment. In addition to the chemotherapeutic effect, CDDP elevates the intracellular H2O2 level through cascade reactions, enabling the persistent conversion of H2O2 to highly cytotoxic •OH through the Fenton reaction between H2O2 and Fe2+, which endows the nanocomplexes with hydroxyl-radical-generation ability and enhances the chemotherapeutic efficacy. Notably, the nanocomplexes as hydroxyl-radical nanogenerators can reverse immunologically “cold” tumors to “hot” tumors by triggering immunogenic tumor cell death and enhance the therapeutic efficacy in combination with ICBs (Apt). Therefore, our study is expected to provide a reasonable treatment paradigm for NSCLC by utilizing the homologous-targeted and tumor microenvironment-activated hydroxyl radical nanogenerator to enhance chemoimmunotherapy.