DFO-loaded PDA nanoparticles facilitated 3D stem cell spheroids for diabetic wound repair by normalizing the pathological microenvironment

Diabetic wounds represent a prevalent and challenging complication of diabetes, characterized by compromised immune function, chronic inflammation, oxidative stress, and impaired revascularization, all of which impede normal wound healing. Despite the high therapeutic potential of 3D stem cell spheroids, owing to their structural and functional advantages, the complex microenvironment encountered post-transplantation significantly diminishes their survival and efficacy. This study presents a novel therapeutic strategy that integrates three-dimensional adipose-derived stem cell spheroids (3D-ADSCs) with desferrioxamine-loaded mesoporous polydopamine nanoparticles (M@D), encapsulated within a gelatin methacrylamide (GelMA) hydrogel scaffold, creating a functional bio-composite. The M@D nanoparticles are designed to scavenge reactive oxygen species (ROS) and provide sustained release of desferrioxamine mesylate (DFO), thereby mitigating oxidative stress, fostering angiogenesis, and improving the local wound microenvironment. This enhanced environment significantly promotes the survival, paracrine activity, and regenerative capacity of 3D-ADSCs spheroids. In turn, these spheroids exert potent paracrine, anti-inflammatory, and immunomodulatory effects, pivotal in tissue repair. The synergistic interaction between M@D nanoparticles and 3D-ADSCs within the GelMA hydrogel not only alleviates oxidative stress-induced cellular damage but also enhances vascularization and nutrient supply, thereby accelerating diabetic wound healing. These results underscore the promising potential of combining cell therapy with material science to develop innovative approaches for diabetic wound management.