Burn blister fluid–derived extracellular vesicles synergistically delivered via hydrogel for integrated pain relief, inflammation control, vascularization, and scar mitigation in diabetic burn wounds

Diabetic scald wounds exist within a hyperglycaemic microenvironment characterised by persistent inflammation, oxidative stress dysregulation, impaired angiogenesis, restricted cell proliferation and migration, and disordered collagen deposition. These wounds are susceptible to bacterial colonisation and biofilm formation, leading to delayed healing, progressive infection, and pathological scarring. In this study, we developed a microenvironment-responsive multifunctional hydrogel, CK@EVs-AB-Co, with antibacterial, anti-inflammatory, analgesic, proangiogenic, and anti-scarring properties. Burn blister fluid-derived small extracellular vesicles (BBF-sEVs) and a cobalt-based metal-organic framework co-loaded with borneol and astragaloside (AB-Co) were embedded in an oxidised konjac glucomannan-carboxymethyl chitosan polysaccharide hydrogel. The resulting material was injectable, self-healing, tissue-adhesive, and interconnectedly porous. The acidic inflammatory milieu of the wound triggered controlled hydrogel degradation and sequential cargo release. In vitro, CK@EVs-AB-Co suppressed NF-κB activation and induced macrophage polarisation toward the M2 phenotype, thereby restoring an anti-inflammatory microenvironment. AB-Co inhibited bacterial growth and disrupted biofilm formation. BBF-sEVs and astragaloside synergistically promoted the proliferation and migration of repair-associated cells. Borneol has analgesic and penetration-enhancing effects. Sustained Co 2+ release allevated hypoxia and promoted angiogenesis. The hydrogel also downregulated the Piezo1-Smad2/3-TAZ signalling axis, reduced TGF-β and CTGF expression, optimised the type I/type III collagen ratio, and restrained excessive fibroblast-to-myofibroblast transition. In a rat model of diabetic scald injury, CK@EVs-AB-Co accelerated wound closure, promoted epidermal and vascular regeneration, improved collagen organisation, and reduced scar formation. It also downregulated COX-2 and inhibited pathological nerve sprouting, thereby alleviating hypersensitivity. Collectively, CK@EVs-AB-Co improved the pathological microenvironment of diabetic scald wounds through wound-adaptive release, antibacterial activity, immunomodulation, analgesia, angiogenesis promotion, and collagen remodelling. This bioactive hydrogel represents a promising therapeutic strategy for refractory diabetic thermal wounds. A pH-responsive polysaccharide hydrogel CK@EVs-AB-Co incorporating burn blister fluid-derived sEVs and borneol/astragaloside-loaded Co-MOF was engineered for diabetic deep scald wounds. Upon acidic stimulation, sequential release of bioactive components remodels the wound microenvironment via antibacterial activity, macrophage polarization, analgesia, angiogenesis promotion and collagen remodelling, accelerating wound healing and attenuating scarring.