Mitochondria-targeted pH/glucose dual-responsive ZIF-8 nanocarrier Co-delivering GOX and BBR for synergistic antitumor therapy

Colorectal cancer (CRC), a leading cause of cancer-related mortality, remains challenging due to drug resistance, insufficient targeting, and systemic toxicity. We engineered a pH/glucose dual-responsive zeolitic imidazolate framework-8 (ZIF-8) nanocarrier for the co-delivery of berberine (BBR) and glucose oxidase (GO X ). BBR and GO X were encapsulated into ZIF-8 nanoparticles via one-pot synthesis and subsequent surface modification with polyethylene glycol–folic acid (PEG–FA), yielding BBR@GO X @ZIF-8–FA (BGZF). At pH 5.4, BBR and GO X release was approximately 74% and 69%, respectively. Cellular uptake and JC-1 assays revealed that the delocalized positive charge of the nanoparticles enhanced mitochondrial targeting, synergizing with GO X -mediated glucose depletion for amplified starvation therapy. Reactive oxygen species (ROS) quantification showed that BBR and GO X synergistically exacerbated oxidative stress, resulting in higher levels of ROS than those observed with monotherapy. Mechanistically, BGZF induced apoptosis through dual pathways: endogenous mitochondrial dysfunction and exogenous ROS overproduction. BGZF’s tumor-specific targeting capabilities were validated in vivo , demonstrating FA-mediated active homing and prolonged biosafety with negligible systemic toxicity. This research pioneers a dual-responsive nanoplatform that integrates mitochondrial targeting and cascade catalytic amplification to achieve synergistic antitumor effects between BBR and GO X , offering a novel paradigm for CRC treatment.