Water-responsive injectable hydrogel achieving rapid in situ gelation and long-term colonic mucoadhesion for...

Gut microbiota dysbiosis is a critical factor in numerous diseases, yet current fecal microbiota (FM) transplantation therapies suffer from poor retention and inconsistent engraftment due to harsh gastric conditions or rapid clearance by bowel peristalsis. Herein, we report a thioester pre-crosslinked, low-viscosity injectable sol (Alg-NHS@αLA) formulated by directly mixing α-lipoic acid (αLA) and N-hydroxysuccinimide ester-modified sodium alginate (Alg-NHS) in a biocompatible polyethylene glycol solvent. This formulation remains flowable for minimally invasive transanal administration. Critically, upon contact with the wet colonic mucosa, tissue-derived water triggers a rapid ring-opening polymerization of αLA, inducing an in situ sol-gel transition to form a robust hydrogel network. Simultaneously, abundant carboxyl groups and unreacted NHS esters establish strong hydrogen bonds and covalent linkages with the mucosal surface, enabling robust and durable wet adhesion that conventional injectables fail to achieve. More importantly, this hydrogel harnesses continuous mucus secretion to facilitate conformal coating, achieving exceptional long-term retention exceeding 72 h while preserving the viability of the incorporated microbiota. The translational potential of this platform is validated through successful endoscopic delivery in a porcine model. By integrating rapid water-triggered gelation with robust mucosal adhesion, our Alg-NHS@αLA/FM system significantly enhances FM transplantation efficacy in a mouse colitis model, offering a promising strategy for colonic microbiome-based therapeutics.