Improving wound healing function and storage stability of stem cell-derived extracellular vesicles via lyophilized hyaluronic acid formulation

Although therapeutic extracellular vesicles (EVs) hold great promise for clinical applications, their limited targeting efficiency and poor storage stability remain critical barriers to clinical translation. Here, we present a lyophilized hyaluronic acid (HA)–coated formulation of EVs derived from human adipose stem cells, engineered to enhance both therapeutic efficacy and long-term preservation. This formulation leverages the natural affinity between HA and the CD44 proteins expressed on the EV membranes, forming stable HA-EV complexes that remain intact following lyophilization and rehydration. These HA-EVs exhibited superior targeting of CD44-expressing cells, including pro-inflammatory macrophages and senescent dermal fibroblasts, thereby effectively suppressing inflammatory responses and restoring fibroblast function in a wound-healing mouse model. Notably, HA-EVs significantly accelerate wound healing by promoting collagen synthesis within the dermal layer, outperforming bare EVs. Furthermore, HA served as an effective cryoprotectant, preserving the physicochemical and biological integrity of EVs for at least six months at 4 ℃. Taken together, our results establish lyophilized HA–EVs as a robust and clinically translatable platform that integrates cell-specific targeting with long-term storage stability for regenerative medicine applications.