A thiol-rich immunomodulatory injectable hydrogel suppresses endometrial fibrosis to restore fertilization.

Endometrial fibrosis disrupts the uterine microenvironment and is a major cause of intrauterine adhesion (IUA) and infertility. Postoperative barriers are commonly used after adhesiolysis, but most act as passive spacers and do not actively remodel the fibrotic inflammatory niche. Here, we report a thiol-rich immunomodulatory injectable hydrogel (TR-gel) that forms in situ through Michael addition between acrylated hyaluronic acid and thiolated hyaluronic acid. The hydrogel conformally adheres to injured endometrium, provides tissue-matched mechanics and controlled biodegradation, and retains abundant thiol groups that create a reductive microenvironment. TR-gel scavenged reactive oxygen species, suppressed nuclear factor κB activation, promoted macrophage polarization toward a proregenerative M2 phenotype, and reduced inflammatory and fibrotic signaling. In a rat IUA model, TR-gel decreased collagen deposition, promoted angiogenesis, restored glandular architecture and embryo receptivity, and improved the fertility rate from 25.0 to 62.5%. These findings provide preclinical evidence that a thiol-rich immunomodulatory hydrogel can combine physical barrier function with microenvironmental regulation to support endometrial regeneration.