A cell-free TLR5high MSC membrane nanoparticle therapy for Crohn's disease: Targeted immunomodulation via the flagellin/TLR5 axis

作者：Yuanyuan Xie, Yu Li, Congwang Xu, Wenting Zhang, Yue Jiang, Liudi Wang, Yingjie Tang, Qing Sun, Hui Yang, Xiaoli Mai, Pingping Shen, Bin Wang · 发表于：Journal of Controlled Release · 年份：2025 · DOI：10.1016/j.jconrel.2025.114121 · 被引用次数：4 · 研究领域：Cancer Immunotherapy and Biomarkers、Mesenchymal stem cell research、Immune cells in cancer

Inflammatory bowel disease (IBD), including Crohn's disease (CD; Th1/Th17-driven) and ulcerative colitis (Th2-skewed), lacks therapies correcting T-cell imbalance. Current cytokine-focused treatments remain ineffective, while mesenchymal stromal cells (MSCs) therapies are hindered by inherent heterogeneity and challenges related to cell viability maintenance, batch-to-batch consistency, and standardization. This study aimed to (Kaplan, 2015 (1)) identify MSCs subtypes targeting CD pathology, Sebastian and Siegmund (2024) (2) create MSCs-mimicking nanoparticles, and (Li et al., 2016 (3)) propose a “deconstructed cell therapy” framework. Using colon datasets and CD blood samples, Th1/Th17-macrophage dysregulation was mapped. Transcriptomic screening of eight MSCs sources identified dental pulp-derived TLR5 high -MSCs as superior Th1/Th17 inhibitors compared to umbilical cord TLR5 low -MSCs. In colitis models, TLR5 high -MSCs intercepted gut flagellin (Fla), blocking macrophage TLR5/NF-κB to restore T-cell balance. Decellularized MSCs membranes were engineered into nanovesicles (TLR5 high -CMNP), which showed 3.7-fold higher Fla. affinity than antibodies and suppressed Th1/Th17 activity in vitro. In murine colitis, TLR5 high -CMNP achieved comparable efficacy to MSCs (e.g., 68.9 % reduction in MPO scores), while avoiding challenges associated with live-cell administration — such as embolism occurrence (0 % vs. 24 % in MSCs), need for viability maintenance, and potential variabil...