Advanced regenerative solutions in diabetic foot ulcer therapy: delivery of mesenchymal stem cells in injectable hydrogels

Diabetic foot ulcers (DFUs) are a severe complication of diabetes characterized by impaired healing driven by oxidative stress, chronic inflammation, reduced angiogenesis, and neuropathy, leading to high risks of infection and amputation. Current therapies remain insufficient, necessitating advanced regenerative approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential through immunomodulation, angiogenesis, and extracellular matrix remodeling; however, their clinical application is limited by poor survival and retention, as well as potential safety concerns. Increasing evidence indicates that MSC-derived exosomes play a central role in mediating these therapeutic effects via paracrine signaling, delivering bioactive cargos such as microRNAs, proteins, and cytokines that regulate immune responses, angiogenesis, and tissue regeneration with lower immunogenicity and improved stability compared to cell-based therapies. Injectable hydrogels have emerged as biomimetic platforms that not only enhance MSC viability and retention but also provide an optimal delivery system for exosomes by protecting them from degradation and enabling sustained, localized release within the wound microenvironment. The integration of MSC-derived exosomes with hydrogel systems represents a synergistic strategy that simultaneously addresses multiple pathological barriers in DFUs, including inflammation, oxidative stress, and impaired vascularization. This review highlights recent advances in hydrogel-based delivery systems for MSCs and, importantly, MSC-derived exosomes, with a particular emphasis on their combined therapeutic potential in diabetic wound healing. Furthermore, emerging smart and stimuli-responsive hydrogels are discussed as next-generation platforms for optimizing exosome delivery and improving clinical outcomes in DFUs.