A pH-responsive hyaluronic acid hydrogel facilitates lesion-localized integrin α5β1 agonism to attenuate osteopontin signaling and fibrosis in intrauterine adhesions.

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.