Surface-engineered chlorella alleviated hypoxic tumor microenvironment for enhanced chemotherapy and immunotherapy of first-line drugs

Abstract

A large number of chemotherapeutic and immunotherapeutic agents have been shown to be less effective when exposed to a hypoxic solid tumor. The tumor hypoxia microenvironment contributes to multidrug resistance and immunosuppression, and current delivery of oxygen or enzyme to alleviate hypoxic microenvironment is often limited by the oxygen supplying capacity of material-based carriers and short window of oxygen production. Herein, macrophage membrane coated chlorella (M-Chl) is constructed for targeted delivery to the solid tumor and sustainable oxygen production via photosynthesis, which provides a new general strategy to overcome tumor hypoxia and improve chemotherapy and immunotherapy. The camouflaged strategy via macrophage membrane coating enhances tumor accumulation and retention of Chl due to the inflammatory homing effects of macrophage membrane, which contributes to long term oxygen production for at least 6 days with one dose of Chl, resulting in efficient downregulation of tumor HIF-1α. In vivo antitumor therapy in mice shows that M-Chl enhances the chemotherapeutic efficacy of doxorubicin via inhibiting hypoxia-mediated overexpression of drug efflux proteins, and also improves the poor immunotherapeutic performance of T cell activation agent, anti-CTLA-4 antibody, via downregulating hypoxia-mediated immunosuppressive proteins. Thus, M-Chl may serve as an important adjuvant for enhancing the therapeutic efficacy of clinical antitumor drugs against solid tumors.