Lactobacillus-Loaded Bioadhesive Hydrogel with Prolonged Retention and Microenvironmental Remodeling for Endometrial Repair and Fertility Restoration.

Endometrial injury often causes inadequate regeneration and infertility, yet current hydrogels fail to meet the dual demands of sustained intrauterine retention and effective pro-regeneration abilities for endometrial repair. Herein, we have developed a bioactive adhesive hydrogel (LAT@L) by facilely integrating three natural medicinal molecules, α-lipoic acid (LA), L-arginine (Arg), and tannic acid (TA) with Lactobacillus johnsonii (L. johnsonii), which exhibits long-term intrauterine retention and microenvironment modulation to promote endometrial repair. Through the spontaneous formation of covalent bonds, hydrogen bonds, and electrostatic interactions among LA, TA, and Arg, a LAT@L hydrogel with a stable network can be prepared via one-pot mixing. Meanwhile, LAT@L hydrogel with adhesive functional groups can also firmly adhere to the uterine surfaces via those multiple interactions. The excellent cohesion and adhesion synergistically enable an intrauterine retention exceeding 14 days. Concurrently, leveraging the anti-inflammatory and antioxidant properties of LA, TA, and Arg, together with the microbiota-modulating activity of L. johnsonii, LAT@L hydrogel effectively reprograms the local microenvironment into a pro-regenerative state. Benefiting from the prolonged intrauterine retention and multifaceted microenvironmental modulation, our LAT@L hydrogel significantly enhances endometrial repair and promotes the recovery of fertility in a rat model of endometrial injury, holding substantial potential for clinical translation.