Dual inhibition of glycolysis and epigenetics via a nanodelivery system for colorectal cancer treatment.

Colorectal cancer (COAD) is characterized by altered metabolism and epigenetic regulation, driving tumor progression and therapeutic resistance. Here, we developed a dual-drug nanodelivery system, SD@MSN-glu, co-encapsulating shikonin (SHK, a glycolysis inhibitor) and dBET6 (a BRD4 degrader) within dextran-modified mesoporous silica nanoparticles. Characterization confirmed uniform spherical morphology, appropriate drug loading, and good short-term stability. The dextran coating hydrolyzes in the intestine to form a glucose-modified surface, enhancing tumor-specific uptake. SHK inhibits PKM2-mediated glycolysis, while dBET6 promotes BRD4 degradation, preventing metabolic compensation. In vitro, SD@MSN-glu markedly inhibited COAD cell proliferation and induced apoptosis. In vivo, it effectively suppressed tumor growth with minimal toxicity to normal organs. This dual-targeting nanoplatform simultaneously modulates metabolic and epigenetic pathways, providing enhanced therapeutic efficacy with low systemic side effects, highlighting SD@MSN-glu as a promising strategy for colorectal cancer treatment.