Micro–Nano Composite System Combining Mesenchymal Stem Cells and Pirfenidone for Endometrial Regeneration via Microenvironment Remodeling

Endometrial injury remains a leading cause of female infertility, yet current clinical interventions exhibit limited regenerative efficacy. In this study, we developed a micro-nano composite system (G-H/ADSC@PDA/PFD) combining adipose-derived mesenchymal stem cell (ADSC)-laden double-network hydrogel (G-H/ADSC) microspheres with pirfenidone (PFD)-loaded polydopamine (PDA/PFD) nanoparticles to achieve synergistic stem cell and drug delivery. The microspheres were fabricated from gelatin methacryloyl (GelMA) and hyaluronic acid methacryloyl (HAMA) via droplet microfluidic technology, exhibiting favorable mechanical strength and cytocompatibility. They provide a 3D microenvironment that supports ADSC growth, proliferation, and paracrine secretion, thereby enhancing angiogenesis and modulating the inflammatory milieu. Moreover, the incorporated PDA/PFD nanoparticles enhance the adhesion of the composite system to the injured endometrial site, while efficiently scavenging reactive oxygen species. The sustained release of PFD downregulates TGF-β expression, inhibits collagen deposition and fibrotic progression, and further optimizes the regenerative niche for ADSCs. In a rat model of endometrial injury, the G-H/ADSC@PDA/PFD system significantly promoted endometrial regeneration, reduced fibrosis, restored the local microenvironment, and successfully restored fertility. This study introduces a promising combinatorial strategy for the treatment of endometrial injury and infertility.