Ji Wanqing, Wen Jiaming, Tong Nian, Guo Fang, Zheng Jie, Wen Xuejun, Liu Jie, Zhang Ning, Hou Bo
Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, 510623, China.
Department of Obstetrics, Guangdong Women and Children Hospital, Guangzhou, Guangdong Province, 511400, China.
Acta Biomater. 2026 Mar 3. doi: 10.1016/j.actbio.2026.03.001.
Intrauterine adhesion (IUA) features persistent immune-stromal disequilibrium and excessive fibrosis driven by inflammatory macrophages, yet current interventions fail to resolve this dysregulation. We developed an in situ-administered pH-responsive liposomal thiolated hyaluronic acid (HA-SH) hydrogel delivering an α5β1-selective agonist peptide to sustain lesion-localized α5β1 agonism at the injury site. Local α5β1 activation shifts macrophages from a pro-inflammatory toward a pro-repair program and suppresses SPP1 (osteopontin), thereby reducing profibrotic cues to endometrial stromal cells. In a rat IUA model, the platform achieves prolonged lesion retention and sustained local exposure, dampens inflammatory cytokines, reduces collagen deposition, and restores endometrial receptivity. Single-cell RNA-seq further indicates a selective reduction of a dominant Spp1-high macrophage state, accompanied by attenuated SPP1-integrin communication to fibrogenic stromal subsets and a shift of stromal states away from myofibroblast-like programs toward remodeling-associated phenotypes. Together, these results support a macrophage-centered integrin-agonism strategy that couples engineered α5β1 activation with responsive biomaterials to modulate fibrotic remodeling in IUA and related fibro-inflammatory disorders. STATEMENT OF SIGNIFICANCE: Intrauterine adhesion (IUA) remains clinically challenging because current anti-fibrotic and anti-inflammatory strategies fail to correct the persistent macrophage-stromal disequilibrium that drives pathological repair. This study establishes a lesion-restricted, pH-responsive liposomal HA hydrogel that delivers an engineered α5β1-selective agonist peptide directly to lesion-resident macrophages. By precisely activating α5β1, the platform redirects macrophages toward a pro-repair program, suppresses SPP1-mediated pro-fibrotic signaling to stromal cells, and reshapes immune-stromal communication as validated by single-cell RNA-seq. The work provides a mechanistically grounded, macrophage-centered integrin-agonism strategy that couples molecular engineering with responsive biomaterials, offering a translatable approach for treating IUA and broader fibro-inflammatory disorders.
