In Situ Transferrin-Mediated Sandwich-likeTargeting with Engineered Ginger-Derived Extracellular Vesicles forPrecision Oral Chemotherapy of Colorectal Cancer

作者：Weilin Lv, S Li, Zhaohan Wei, Xin Li, Xi Zhang, Shiyi Xu, Zixiang Xie, Yaoli Zhao, Dai Ll, Ziqiao Ding, Muzi Tian, Ruoxi Wang, Liping Huang, Nana Bie, Xiaomin Yang, Fei Xiong, Lu Gan, Tuying Yong · 发表于：ACS Nano · 年份：2026 · DOI：10.1021/acsnano.6c08131 · 研究领域：Extracellular vesicles in disease、Nanoplatforms for cancer theranostics、Nanoparticle-Based Drug Delivery

Oral chemotherapy for colorectal cancer (CRC) is limited by poor tumor selectivity and microenvironment-driven resistance. Addressing these limitations demands materials that integrate tumor-selective targeting with immune microenvironment modulation. Here, clinical analysis of CRC specimens revealed pronounced transferrin (Tf) enrichment in CRC-associated intestinal regions. Guided by this finding, we engineered a gastrointestinal-stable cyclic Tf-binding peptide (cp) with high Tf affinity and constructed cp-modified ginger-derived extracellular vesicles (cp-GEVs) for in situ Tf-mediated sandwich-like targeting. By recruiting endogenous Tf, cp-GEVs established a Tf-mediated bridging interface that selectively engages Tf receptor-overexpressing intestinal epithelium and tumor cells, enabling efficient epithelial transcytosis, tumor-selective accumulation, and deep intratumoral penetration after oral administration. When loaded with irinotecan (CPT-11), CPT@cp-GEVs significantly enhanced intracellular drug delivery and reprogrammed immunosuppressive M2-like tumor-associated macrophages toward a pro-inflammatory phenotype, thereby disrupting cancer stem cell-enriched drug-resistant niches. In AOM/DSS-induced primary CRC models and patient-derived ex vivo systems, CPT@cp-GEVs significantly improved chemotherapeutic efficacy while attenuating resistance. Collectively, this work establishes a Tf-mediated sandwich-like targeting framework for oral cancer therapy, offering a concept...