Platelet Membrane Fragment Self‐Assembled Oral Hydrogel Microspheres for Restoring Intestinal Microvascular Injury

Abstract Non‐invasive management of intestinal microvascular injury with hemorrhage under constant biochemical‐mechanical encroachment of luminal contents is a major clinical challenge. Herein, an oral hydrogel microsphere is designed, encapsulating the platelet membrane fragment self‐assembled nanohydrogel fabricated by double‐crosslinking of methacrylated hyaluronic acid and Rebamipide‐loaded dendrimer (Rng@PMS), for self‐localization of hemorrhagic focus and intensive management of intestinal microvascular injury via suppression of inflammation‐mediated tissue injury and reintegration of the damaged mucosal barrier. The results indicate that Rng@PMS effectively adheres to exposed collagen on injured microvasculature and attaches to over 90% of activated macrophages within 10 min, endowing Rng@PMS with a significantly prolonged enteral dwell time (over 24 hours). Importantly, Rng@PMS generated from alginate is designed for oral colon‐targeted delivery to avoid the erosion of gastrointestinal contaminants. In vivo study reveals oral administration of microspheres in murine hematochezia model upregulates the intestinal barrier proteins zonula occludens‐1, Occludin, and muc2, and inhibits infiltration of neutrophils, dendritic cells, and macrophages in hemorrhagic foci, thereby reducing the hematochezia score from 4 to 0.8, and the pathology score from 5.3 to 0.5. Oral microspheres for in situ management of intestinal microvascular injury may be applicable more broadly to noninvasively treat diseases with symptoms of mucosal hemorrhage.