Probiotic‐Derived Vesicles Rectally Delivered via Thermo‐Gelling Copolymer Promote Mucosal Healing and Reduce Inflammation in Ulcerative Colitis

ABSTRACT Ulcerative colitis remains challenging to treat due to the need for localized control of inflammation, restoration of mucosal integrity, and avoidance of systemic toxicity. Here, we report a rectally administered, sprayable, thermo‐responsive hyaluronic acid‐based copolymer platform for the localized co‐delivery of probiotic‐derived extracellular vesicles (ProEVs) and 5‐aminosalicylic acid. This system enables enhanced retention and sustained presentation of therapeutics at inflamed colonic sites. The combined formulation demonstrates improved therapeutic efficacy compared to individual treatments, promoting mucosal recovery and intestinal homeostasis. Mechanistically, the platform modulates inflammatory responses, supports epithelial barrier function, and contributes to microbiota rebalancing. Notably, extracellular vesicles provide a more effective and consistent therapeutic modality compared to live probiotics. Importantly, the formulation is designed for clinical translation, offering localized administration, minimal toxicity, and stability upon lyophilization, enabling off‐the‐shelf use. These findings highlight the potential of integrating extracellular vesicles with biomaterial‐based delivery systems as a multifunctional therapeutic strategy for inflammatory bowel disease.