Li Ling, Yao Zhicheng, Salimian Kevan J, Kong Jiayuan, Zaheer Atif, Parian Alyssa, Gearhart Susan L, Mao Hai-Quan, Selaru Florin M
Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
Adv Healthc Mater. 2025 Mar;14(7):e2402292. doi: 10.1002/adhm.202402292. Epub 2024 Sep 6.
Perianal fistulas represent a common, aggressive, and disabling complication of Crohn's disease (CD). Despite recent drug developments, novel surgical interventions as well as multidisciplinary treatment approaches, the outcome is dismal, with >50% therapy failure rates. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) offer potential therapeutic benefits for treating fistulizing CD, due to the pro-regenerative paracrine signals. However, a significant obstacle to clinical translation of EV-based therapy is the rapid clearance and short half-life of EVs in vivo. Here, an injectable, biodegradable nanofiber-hydrogel composite (NHC) microgel matrix that serves as a carrier to deliver MSC-derived EVs to a rat model of CD perianal fistula (PAF) is reported. It is found that EV-loaded NHC (EV-NHC) yields the best fistula healing when compared to other treatment arms. The MRI assessment reveals that the EV-NHC reduces inflammation at the fistula site and promotes tissue healing. The enhanced therapeutic outcomes are contributed by extended local retention and sustained release of EVs by NHC. In addition, the EV-NHC effectively reduces inflammation at the fistula site and promotes tissue healing and regeneration via macrophage polarization and neo-vascularization. This EV-NHC platform provides an off-the-shelf solution that facilitates its clinical translation.
肛周瘘是克罗恩病（CD）常见、侵袭性且致残的并发症。尽管近期有药物研发、新型手术干预以及多学科治疗方法，但治疗结果仍令人沮丧，治疗失败率超过50%。间充质干细胞（MSC）衍生的细胞外囊泡（EV）由于其促再生旁分泌信号，为治疗瘘管型CD提供了潜在的治疗益处。然而，基于EV的疗法临床转化的一个重大障碍是EV在体内的快速清除和短半衰期。在此，报道了一种可注射、可生物降解的纳米纤维-水凝胶复合材料（NHC）微凝胶基质，它作为载体将MSC衍生的EV递送至CD肛周瘘（PAF）大鼠模型。研究发现，与其他治疗组相比，负载EV的NHC（EV-NHC）产生了最佳的瘘管愈合效果。MRI评估显示，EV-NHC减轻了瘘管部位的炎症并促进了组织愈合。增强的治疗效果得益于NHC对EV的延长局部保留和持续释放。此外，EV-NHC通过巨噬细胞极化和新血管形成有效减轻了瘘管部位的炎症并促进了组织愈合和再生。这个EV-NHC平台提供了一种现成的解决方案，便于其临床转化。
