Hybrid membrane based biomimetic nanodrug with high-efficient melanoma-homing and NIR-II laser-amplified peroxynitrite boost properties for enhancing antitumor therapy via effective immunoactivation

Owing to the excellent stability, anticancer activity and immunogenicity, peroxynitrite (ONOO^-) has been gained enormous interests in cancer therapy. Nevertheless, precise delivery and control release of ONOO^- in tumors remains a big challenge. Herein, B16F10 cancer cell membrane/liposome hybrid membrane (CM-Lip) based biomimetic nanodrug with high-efficient tumor-homing and NIR-II laser controlled ONOO^- boost properties was designed for melanoma treatment. Briefly, NIR-II molecule IR1061, NO donor BNN6 and β-lapachone (Lapa) were firstly encapsulated in the heat-responsive palmitoyl phosphatidylcholine/cholesterol liposome, followed by fusion with B16F10 cell membrane (CM) to obtain biomimetic CM-Lip@(IR/BNN6/Lapa). The hybrid membrane-based nanodrug displayed excellent biocompatibility and melanoma-targeting efficiency. Upon 1064 nm laser irradiation, the mild photothermal effect of CM-Lip@(IR/BNN6/Lapa) firstly triggered the release of NO and Lapa, which subsequently catalyzed the quinone oxidoreductase 1 (NQO1) overexpressed in tumors to produce O₂^•-, finally caused intraturmal ONOO^- boost via cascade reaction. The boosted ONOO^- could effectively inhibit melanoma by ways of triggering mitochondrion-mediated apoptotic pathway, upregulating 3-nitrotyrosine expression, inducing DNA damage and inhibiting DNA repair enzyme expression of poly (ADP-ribose) polymerase 1 (PARP-1). Moreover, ONOO^- displayed excellent immunoactivation and immunomodulation activities by effectively inducing immunogenic tumor cell death, promoting dendritic cells maturation, increasing cytotoxic T lymphocytes expression and repolarizing M1-phenotype macrophages.