Phase Separation‐Induced Surface Protuberances in Hydrogel Particles for Enhanced Intestinal Retention

Abstract The surface roughness of microparticles enhances their biological interactions; however, engineering such features in fully assembled polymeric membranes remains challenging. Inspired by natural budding phenomena, this study developed solvent‐free tannic acid–polyethylene oxide (TA‐PEO) microcapsules with tunable surface roughness, achieved through an interfacial instability mechanism triggered by bovine serum albumin (BSA). The microfluidic platform enables precise control of microcapsule size and monodispersity through vibration frequency and flow rate optimization. The dynamic hydrogen‐bonded TA‐PEO network facilitates pH‐responsive drug release, which can be tuned from burst to sustained modes through polyethylene oxide (PEO) concentration adjustments. Competitive BSA adsorption at the capsule interface generates localized “soft patches,” triggering spontaneous budding under osmotic gradients. This roughness significantly enhances intestinal adhesion, with budding microcapsules exhibiting prolonged retention in vivo compared with their smooth counterparts. In a mouse model of inflammatory bowel disease (IBD) induced by dextran sulfate sodium (DSS), probiotic‐loaded budding microcapsules restored colon length, epithelial integrity, and body weight, outperforming free probiotics and non‐budding controls. In summary, this study established a solvent‐free strategy for engineering adhesive rough‐surfaced microcapsules, highlighting their potential for targeted mucosal delivery and gastrointestinal therapeutics.