A biodegradable nanodrug with highly efficient treatment effect by remodeling tumor microenvironment and manipulating energy metabolism against colorectal cancer

Cisplatin (CDDP), a widely used chemotherapy drug for colorectal cancer, suffers from rapid clearance, resistance, and nonspecific delivery. Meanwhile, the sophisticated tumor microenvironments (TME), such as hypoxia, elevated glutathione (GSH) level, and rapid energy metabolism, result in an unsatisfactory treatment effectiveness of chemotherapy. Herein, a TME-responsive nanoplatform was constructed by loading CDDP and coating with a manganese dioxide (MnO2) shell on the zeolitic imidazolate framework, and finally modified with hyaluronic acid (HA) as a targeting molecule (ZIF-90@CDDP@MnO2@HA) for the combined chemotherapy/chemodynamic therapy (CDT)/starvation therapy of colorectal cancer. The TME-responsive drug release significantly improves the therapeutic efficacy of chemotherapy. On the one hand, the MnO2 shell depletes GSH to inhibit CDDP detoxification and reactive oxygen species clearance, and the released Mn2+ could achieve CDT. On the other hand, the downregulating expression of hypoxia-inducible transcription factor 1α by oxygen generation not only reverses chemotherapy resistance but also inhibits aerobic glycolysis by downregulating expression of hexokinase 2 and glucose transportase-1, further contributing to starvation therapy. In addition, Zn2+ released from ZIF-90 causes mitochondrial damage, further inhibiting adenosine triphosphate production in concert with glycolysis inhibition to enhance starvation therapy. This synergistic treatment strategy exhibits an excellent antitumor effect in vitro and in vivo, which opens a new way to enhance the antitumor efficacy of CDDP-based chemotherapy for colorectal cancer.