Blastocyst Structure-Inspired Core-Shell Stem Cell Microspheres with Hyperoside Delivery for Endometrial Regeneration

Endometrial injury and subsequent intrauterine adhesions (IUA) challenge reproductive health. Inspired by the blastocyst structure, we developed a core-shell microsphere (HBM) for endometrial regeneration via the dual delivery of bone marrow-derived mesenchymal stem cells (BMSCs) and hyperoside (HYP). Fabricated by microfluidic electrospray, HBM feature a sodium alginate (ALG) shell embedded with Fe₃O₄@MgSiO₃ magnetic nanoparticle for targeted delivery and a carboxymethyl cellulose (CMC) core encapsulating BMSCs. This design enables spatiotemporal release: shell-HYP modulates early inflammation by polarizing macrophages toward the anti-inflammatory M2 phenotype, whereas BMSCs in the core promote angiogenesis and tissue repair through paracrine signaling. In vitro, HBMs enhanced human umbilical vein endothelial cell proliferation, angiogenesis, and inflammation inhibition. In a rat IUA model, HBM significantly restored endometrial thickness, increases gland numbers, and reduces collagen deposition.  While also regulating inflammatory microenvironment and enhancing endometrial receptivity. Transcriptomic profiling reveals the activation of immune-modulatory and tissue repair pathways in HBM. This synergistic strategy, combining immunomodulation, stem cell therapy, and magnetic targeting, offers a promising approach for efficient endometrial regeneration and IUA prevention, addressing critical gaps in current clinical.