Self-healing and pH-responsive bioactive hydrogel dressing loaded with Ramulus Mori-derived exosome-like nanovesicles accelerates diabetic wound healing

Diabetic wounds, characterized by a complex pathological microenvironment of persistent inflammation, impaired angiogenesis, and dysfunctional extracellular matrix (ECM) remodeling, pose a significant clinical challenge due to the lack of highly effective treatments. Given that simultaneous modulation of these interconnected pathological processes is crucial for effective healing, a multifunctional hydrogel dressing (SQS-GEL) with self-healing and pH-responsive properties was engineered for the targeted delivery of exosome-like nanovesicles derived from Ramulus Mori (SZENs). This dual-network hydrogel was constructed through dynamic Schiff base bonds between oxidized mulberry branch polysaccharides and quaternized chitosan, further reinforced by hydrogen bonding interactions with silk fibroin. The resulting SQS-GEL exhibited excellent mechanical strength, injectability, and autonomous self-healing capability. Crucially, it demonstrated intelligent pH-dependent degradation property, enabling controlled release of SZENs specifically in the acidic wound microenvironment. In vitro studies revealed that the SZENs@SQS-GEL system synergistically enhanced antioxidant and anti-inflammatory activities, while potently promoting cell proliferation, migration, and angiogenesis. In a streptozotocin-induced diabetic mouse model, the hydrogel significantly prolonged SZENs retention at the wound site. This led to multifaceted therapeutic outcomes: effective bacterial inhibition, alleviation of excessive inflammation, stimulation of granulation tissue formation, enhanced angiogenesis, and facilitated orderly ECM deposition. Consequently, SZENs@SQS-GEL dramatically accelerated wound closure and promoted scarless healing. This study presents a novel and integrated therapeutic strategy, highlighting the great translational potential of the SZENs@SQS-GEL system for managing refractory diabetic wounds and other inflammatory tissue disorders.