An Injectable Nanocomposite Hydrogel for Efficient Triple Cancer Starvation Therapy In Vivo

ABSTRACT The anabolism of malignant tumor cells provides a stable energy supply for their proliferation. Therefore, restricting nutrient/energy supply may be an effective strategy to inhibit tumor growth. Herein, a novel therapeutic approach—triple starvation therapy—is illustrated by combretastatin A‐4 phosphate (CA‐4P)/glucose oxidase (GOx)/3‐PO@ZIF‐8@HA@hydrogel (termed CGP@H). Specifically, CA‐4P can block the nutrient supply to tumors by cutting off tumor blood vessels. GOx can consume glucose by converting glucose to gluconic acid and hydrogen peroxide in tumor tissue. Upon endocytosis of 3‐PO@ZIF‐8@HA nanoparticles by tumor cells, the released 3‐(3‐pyridyl)‐1‐(4‐pyridyl)‐2‐propen‐1‐one (3‐PO) effectively inhibits the activity of the PFKFB3 protein, thereby blocking glycolysis and consequently restricting energy supply. This study presents a straightforward yet highly effective strategy to restrict tumor nutrient/energy supply on three distinct levels. Moreover, it offers a novel platform for achieving more potent cancer starvation therapy through the integration of multiple nutrient/energy depletion approaches.