Human ES cell-derived MSC spheroids encapsulated in polydopamine nanoparticle-modified GelMA hydrogel enhance diabetic wound healing.

Mesenchymal stromal cell (MSC)-based strategies hold promises for treating diabetic foot ulcers. However, the hostile microenvironment of the lesions characterized by hypoxia, oxidative stress, and chronic inflammation impairs the survival and efficacy of transplanted MSCs. Here, we developed a composite bio-dressing by integrating MSC spheroid (Sp) derived from human embryonic stem cells via trophoblast intermediates (T-MSC) with gelatin methacryloyl hydrogel (Gm) and polydopamine nanoparticles (Pn). The GmPn matrix exhibited excellent adaptability, adhesion, porosity, biodegradability, and biocompatibility. Compared to monolayer-cultured T-MSCs, T-MSC Sp with scalable production via hanging drop demonstrated greater resilience to hypoxia and enhanced the migration and tube formation of vascular endothelial cells by secreting higher levels of chemokines and growth factors, verified by RNA-Seq and cytokine array. Furthermore, the combination of T-MSC Sp with Pn provided superior antioxidant, cell protection, and inflammation-regulatory effects compared to either component alone. The integration of T-MSC Sp, Gm, and Pn resulted in a bio-dressing termed SpGmPn, which accelerated wound area closer compared to Sp alone, owing to the synergistic effects of its components in stage-dependent immunomodulation and enhanced tissue regeneration. Thus, SpGmPn represents a promising and scalable therapeutic strategy for enhancing diabetic wound repair beyond the capabilities of T-MSC Sp alone.