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Background Colorectal cancer (CRC), a leading cause of cancer-related mortality, remains challenging due to drug resistance, insufficient targeting, and systemic toxicity.Methods We engineered a pH/glucose dual-responsive zeolitic imidazolate framework-8 (ZIF-8) nanocarrier ( IDDF2026-ABS-0394 Figure 1. Preparation of BGZF nanoparticles for anti-CRC therapy) for the co-delivery of berberine (BBR) and glucose oxidase (GOX).Results 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@GOX@ZIF-8–FA (BGZF). At pH 5.4, BBR and GOX release were approximately 74% and 69%, respectively (IDDF2026-ABS-0394 Figure 2. Physicochemical characterization and glucose-responsive release behavior of BGZF). Cellular uptake and JC-1 assays revealed that the delocalized positive charge of the nanoparticles enhanced mitochondrial targeting, synergizing with GOX-mediated glucose depletion for amplified starvation therapy (IDDF2026-ABS-0394 Figure 3. In vitro assessment of BGZF anti-cancer mechanisms and glucose-mediated ROS generation). Reactive oxygen species (ROS) quantification showed that BBR and GOX 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 (IDDF2026-ABS-0394 Figure 4. Mechanistic insights into BGZF regulation of AMPKmtor pathway and apoptotic markers, IDDF2026-ABS-0394 Figure 5. Oxidative stress, mitochondrial impairment, and folate-mediated). BGZF’s tumor-specific targeting capabilities were validated in vivo, demonstrating FA-mediated active homing and prolonged biosafety with negligible systemic toxicity (IDDF2026-ABS-0394 Figure 6. Subcellular targeting to mitochondria and tumor accumulation of BGZF).Conclusions 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.Abstract IDDF2026-ABS-0394 Figure 1Abstract IDDF2026-ABS-0394 Figure 2Abstract IDDF2026-ABS-0394 Figure 3Abstract IDDF2026-ABS-0394 Figure 4Abstract IDDF2026-ABS-0394 Figure 5Abstract IDDF2026-ABS-0394 Figure 6