Innovative Bio-based Hydrogel Microspheres Micro-Cage for Neutrophil Extracellular Traps Scavenging in Diabetic Wound Healing

Abstract

Neutrophil extracellular traps (NETs) seriously impede diabetic wound healing. The disruption or scavenging of NETs using deoxyribonuclease (DNase) or cationic nanoparticles has been limited by liberating trapped bacteria, short half-life, or potential cytotoxicity. In this study, a positive correlation between the NETs level in diabetic wound exudation and the severity of wound inflammation in diabetic patients is established. Novel NETs scavenging bio-based hydrogel microspheres ‘micro-cage’, termed mPDA-PEI@GelMA, is engineered by integrating methylacrylyl gelatin (GelMA) hydrogel microspheres with cationic polyethyleneimine (PEI)-functionalized mesoporous polydopamine (mPDA). This unique ‘micro-cage’ construct is designed to non-contact scavenge of NETs between nanoparticles and the diabetic wound surface, minimizing biological toxicity and ensuring high biosafety. NETs are introduced into ‘micro-cage’ along with wound exudation, and cationic mPDA-PEI immobilizes them inside the ‘micro-cage’ through a strong binding affinity to the cfDNA web structure. The findings demonstrate that mPDA-PEI@GelMA effectively mitigates pro-inflammatory responses associated with diabetic wounds by scavenging NETs both in vivo and in vitro. This work introduces a novel nanoparticle non-contact NETs scavenging strategy to enhance diabetic wound healing processes, with potential benefits in clinical applications.