Multiple dynamic crosslinked multifunctional hydrogels with glucose/pH dual-responsive ADSC-exosomes-releasing for diabetic wound healing

Background The efficacy of exosomes from adipose-derived stem cells (ADSC-exos) in accelerating diabetic wound healing is limited due to the inflammation and hypoxia of the wound. Thus, the design of microenvironment-responsive ADSC-exos sustained-release hydrogel dressings that maximize the biological role of exosomes and alleviate the inflammation of diabetic wound is essential. Methods In this study, we prepared a glucose/pH dual-responsive multifunctional hydrogel loaded with ADSC-exos based on dynamic dual cross-linking via Schiff bases and phenylboronic esters, with the aim of achieving intelligent release of ADSC-exos in response to the acidic and high-glucose-concentration pathological microenvironment in diabetic wounds. Results This hydrogel showed swelling and degradation characteristics in high glucose/low pH environment, resulting in an increased release of ADSC-exos. The antimicrobial activity and improved mechanical properties of the hydrogel were achieved via the introduction of a second dynamic cross-linking network involving 4-arm SH-poly (ethylene glycol) and Ag+. In a chronic diabetic full-thickness skin wound model, compared with non-responsive ADSC-exos-loaded hydrogels, the dual-responsive hydrogel ameliorated tissue inflammation and increased angiogenesis by promoting the conversion of macrophages to the anti-inflammatory M2 phenotype, showing an increased healing rate. The underlying mechanism revealed that dual-responsive release of ADSC-exos improves the wound microenvironment by inhibiting the Notch/NF-κB/NLRP3 signaling pathway. Conclusion We successfully developed a dual-responsive hydrogel delivery system that responds efficiently to the high-glucose and acidic microenvironment via Notch/NF-κB/NLRP3 signaling pathway, thereby promoting healing of chronic diabetic wounds.