Aptamer-modified 5-fluorouracil encapsulated metal-organic framework nanodrugs for enhanced therapy of colorectal cancer via peroxidative induced cell death

Colorectal cancer (CRC) remains one of the most devastating malignancies worldwide. 5-Fluorouracil (5-FU) is a widely used therapeutic agent in CRC treatment. Here, we report a PTK-7–targeted, MOF-based nanodrug (AFZC) comprising Sgc8 aptamer, 5-FU, and Cu-doped ZIF-8. AFZC was synthesized via stepwise loading and surface functionalization and rigorously characterized by SEM/TEM. Targeting specificity was confirmed in PTK-7–positive colorectal cancer cells: Cy5-Sgc8 showed strong internalization in CRC cells but negligible uptake in normal epithelial cells. Functionally, AFZC suppressed proliferation and lowered 5-FU IC₅₀ across multiple CRC lines, with enhanced apoptosis versus 5-FU alone. Patient-derived organoids demonstrated greater growth inhibition with AFZC than with 5-FU. Transcriptomic profiling of AFZC-treated CRC cells highlighted pro-apoptotic remodeling with upregulation of NECTIN4 and NCF2, and concordant increases by Western blot alongside caspase cleavage. In vivo, AFZC achieved superior tumor control over 5-FU or ZIF-8 in CRC xenografts and a PDX model. No toxicity was found in histopathology of major organs or in liver/renal function markers at the treatment dosage. Collectively, AFZC couples selective PTK-7 targeting, catalytic activity, and sustained drug release to potentiate 5-FU efficacy with a favorable toxicity profile, supporting its translational promise in CRC.