2026-10-12T01:30:53Z https://www.scidb.cn/oai

10.57760/sciencedb.38150 2026-06-01T13:35:58Z

2026-06-01 CEACAM5-Directed Tumor-Selective Delivery of DON Abolishes Gastrointestinal Toxicity and Synergizes with 5-FU in Colorectal Cancer doi:10.57760/sciencedb.38150 en Objective: Colorectal cancer (CRC) causes high cancer-related mortality, and 5-fluorouracil (5-FU) chemotherapy is limited by chemoresistance and toxicities. Although the glutamine inhibitor 6-diazo-5-oxo-l-norleucine (DON) suppresses CRC metabolism and boosts anti-tumor immune, its non-specific distribution induces severe gastrointestinal toxicity, hindering clinical use. This study aimed to develop a precise CRC-targeted DON delivery systemfor safe combination therapy with 5-FU.Methods: TCGA and scRNA-seq databases were mined to screen CRC-specific membrane targets. Immunofluorescence, IHC and Western blot confirmed the specific membrane enrichment of CEACAM5 in CRC. A CEACAM5-targeted DON nanovesicle (aCEA-Nano-DON) was then constructed. Its tumor-targeting ability was verified in vitro in CRC cell lines and patient-derived organoids, and further confirmed in vivo in patient-derived xenograft (PDX) models. These PDX models were subsequently used to evaluate the synergistic antitumor efficacy and systemic biosafety of aCEA-Nano-DON in combination with 5-FU.Results: aCEA-Nano-DON exhibited excellent target specificity, selectively accumulating in CEACAM5-positive CRC cells while showing minimal uptake in normal intestinal tissues. In PDX models, aCEA-Nano-DON plus 5-FU achieved potent anti-tumor effects equivalent to free DON combination. Importantly, the nanoplatform completely eliminated DON-induced systemic and gastrointestinal toxicity, preserving intestinal structure and hepatic and renal function.Conclusion: This targeted nanotherapy overcomes the clinical toxicity barrier of DON. aCEA-Nano-DON enables safe and effective combination with 5-FU, offering a promising translatable metabolic-chemotherapeutic strategy for CEACAM5-positive CRC treatment. Colorectal cancer; DON; CEACAM5-targeted nanovesicles; tumor-selective drug delivery; glutamine metabolism inhibition; patient-derived xenografts (PDXs); toxicity reduction Minshan Wu Yuanhui Wu Haigui Wan Xiaoxia Liu PUBLIC https://creativecommons.org/licenses/by/4.0/ dataset Science Data Bank