GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342942/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342942GEOGSEfalseOral Delivery of R-spondin1-Loaded Small Extracellular Vesicles Activates WNT Signalling Pathway to Accelerate Intestinal Injury Repair and Reverse AgeingThe intestine plays a crucial role in regulating metabolism and immunity, with functional decline occurring during injury and ageing. Stimulating the neogenesis of intestinal stem cells (ISCs) by activating the WNT/β-catenin signalling pathway represents a promising approach for intestinal tissue regeneration and injury repair. However, effective oral delivery of functional WNT signalling agonists to the gut remains challenging. Herein, we report a potent WNT/β-catenin signalling-inducing small extracellular vesicles (sEV) that can be administered orally and present remarkable therapeutic efficacy. We demonstrate that active R-spondin1 (RSPO1) protein can be loaded onto the surface of sEV via heparan sulfate proteoglycans. Notably, sEV-delivered RSPO1 (evRSPO1) effectively induces WNT/β-catenin signalling-inducing activity, enhances ISCs proliferation, and supports intestinal organoid growth in vitro. Importantly, oral administration of evRSPO1 activates the WNT/β-catenin signalling pathway in the cryptic stem cell niche, thereby accelerating tissue repair and regeneration in a radiation-induced intestinal injury model. Furthermore, evRSPO1 treatment induces ISCs proliferation and reverses the intestinal senescence phenotype in aged mice. Collectively, this study establishes evRSPO1 as a potential first-in-class, orally deliverable therapeutic that overcomes biological barriers to activate ISCs, enabling efficient intestinal tissue repair and rejuvenation.2026/08/11GSE342942GSM9943511GSM9943500GSM9943510GSM9943499GSM9943502GSM9943501GSM9943512GSM9943496GSM9943498GSM9943497GSM9943508GSM9943507GSM9943509GSM9943504GSM9943503GSM9943506GSM994350534290342942Mus musculus