A multifunctional DNAzyme-nanozyme cascade system for glucose metabolic reprogramming and theranostics of pancreatic cancer.

To disrupt the glycolytic metabolism vital for pancreatic cancer (PC), we developed a cascade-amplified and PC-targeted nanosystem, HMAD@EP-XQ2d. It integrates a DNAzyme for GLUT1 gene silencing, AuNPs-based nanozymes for catalytic activity, and a HMnO carrier, cloaked in an aptamer-modified erythrocyte membrane. The system actively targets CD71-overexpressing PC cells. Upon accumulation in the tumor microenvironment (TME), the HMnO degrades, initiating a therapeutic cascade: the released Mn serves a dual function-they activate the DNAzyme for upstream blockade of glucose uptake, and act as a contrast agent for magnetic resonance imaging (MRI), enabling real-time monitoring of drug delivery and accumulation; concurrently, the exposed gold nanozymes exert glucose oxidase-like (GOx-like) activity to deplete glucose (downstream depletion) and peroxidase-like (POD-like) activity to convert the resultant HO into cytotoxic hydroxyl radicals (oxidative stress). This three-pronged, synergistic attack on glycolysis induces a severe energy crisis in PC cells. Both in vitro and in vivo studies demonstrate potent antitumor efficacy, favorable biocompatibility, and MRI contrast capability. By integrating gene silencing, enzymatic catalysis, and imaging into a single responsive system triggered by the TME, this all-in-one theranostic platform offers a novel precise metabolic intervention strategy for pancreatic cancer.