Hypoxia-pretreated ADSC-derived exosome-embedded hydrogels promote angiogenesis and accelerate diabetic wound healing

Accumulating reports indicate that adipose-derived stem cell (ADSC)-originating exosomes (ADSC-Exos) provide a potential strategy for diabetic wound repair. However, the disadvantages of exosomes, such as fast decrease of biological activity and unknown biological mechanisms, limit their clinical application. Herein, hypoxia-pretreated ADSC-Exo (ADSC-HExo)-embedded GelMA hydrogels (GelMA-HExo) were developed via non-covalent force and physical embedding. These materials rapidly converted into a gel state under illumination, thereby adapting to irregular diabetic wounds. The regulatory mechanism of circ-Snhg11 delivery by exosomes in accelerating diabetic wound healing was explored. In vitro, GelMA-HExo hydrogels had a loose porous structure, and a stable degradation and expansion rate. In vivo, GelMA-HExo hydrogels promoted wound healing in diabetic mice. In particular, ADSC-HExos had a good therapeutic effect, in which circ-Snhg11 expression was increased. Furthermore, circ-Snhg11-modified ADSC-Exos increased the migratory, proliferative and blood vessel regeneration potential of vascular endothelial cells (ECs). In addition, overexpression (OE) of NFE2L2-HIF1α or inhibition of miR-144-3p-both of which are members of the miR-144-3p/NFE2L2/HIF1α pathway downstream of circ-Snhg11-reversed the therapeutic effects of circ-Snhg11. In summary, this study explored the effects and downstream targets of hypoxic engineered exosome hydrogels in managing diabetic wound repair. These hydrogels are expected to serve as a new approach for clinical treatment and to have application possibilities in other disease areas. STATEMENT OF SIGNIFICANCE: ADSC-Exo treatment can accelerate diabetic wound healing via circRNA delivery. But how to reverse the problems such as poor mechanical properties, low biological activity, short duration of effect and high risk of sudden release of exosomes needs investigation. We constructed exosome-embedded GelMA (GelMA-Exo) hydrogels and found that GelMA-Exo treatment could significantly promote diabetic wound healing. Further study found that exosomes from hypoxia-pretreated ADSCs (ADSC-HExos) had an enhanced therapeutic effect than normal exosomes. The regulation mechanism study found that circ-Snhg11 delivery from GelMA-HExo incremented survival and maintained endothelial cell (EC) function, possibly via the activation of miR-144-3p/NFE2L2/HIF1α signaling. These findings suggest a new therapeutic strategy for patients with diabetic ulcer.