Niosome-mediated melatonin delivery via SilMA/GelMA microneedles promotes healing of sleep deprivation-aggravated oral ulcers

Abstract

Sleep disturbance disrupts immune homeostasis and impairs oral mucosal healing, yet effective local immunomodulatory strategies remain limited. Here, we identify excessive neutrophil extracellular traps (NETs) as a key mediator linking sleep deprivation to delayed oral wound closure. NETs-associated proteases compromise epithelial barrier function and suppress repair cell migration. To address this, we developed a melatonin-loaded niosome-incorporated silk fibroin methacrylate (SilMA)/gelatin methacryloyl (GelMA) composite hydrogel microneedle (Nio-MT@S-G MN) for localized melatonin delivery and regulation of the NETs-associated inflammatory microenvironment. Niosomes achieve efficient encapsulation and sustained melatonin release, while SilMA/GelMA microneedles enable transmucosal administration with favorable mechanical strength. In vitro, Nio-MT@S-G MN promotes keratinocyte migration, reduces NETs marker expression and extracellular DNA release in neutrophils, and alleviates NETs-mediated inhibition of tight junction Zonula occludens-1 (ZO-1) expression. In mice combining sleep deprivation and oral ulcers, local Nio-MT@S-G MN application attenuates NETs deposition and inflammation, restores epithelial barrier proteins, and significantly accelerates ulcer closure. By integrating controlled drug delivery with immune microenvironment regulation, this microneedle provides a translational strategy for treating sleep disorder-aggravated mucosal injuries. It may also be applicable to other chronic wounds characterized by dysregulated neutrophil responses.