Microalgae extracellular vesicles-loaded dual antioxidative and anti-inflammatory hydrogel system for wound healing and peripheral nerve repair in diabetes.

Abstract

Chronic wound healing and peripheral nerve repair in diabetes remain a major clinical challenge due to persistent oxidative stress, inflammation, and impaired tissue regeneration. Here, we developed a multifunctional hydrogel, mEVs@TAgel, for the synergistic delivery of microalgal extracellular vesicles (mEVs) from <i>Haematococcus pluvialis</i> and tannic acid (TA) to address these barriers. mEVs are rich in astaxanthin and functional proteins that target mitochondrial dysfunction and oxidative stress, while TA itself exhibits intrinsic antioxidant and anti-inflammatory properties. The hydrogel exhibits excellent injectability, tissue adhesion, and sustained release of mEVs. <i>In vitro</i>, mEVs@TAgel significantly reduced ROS levels by activating the Nrf2 signaling pathway, enhanced mitochondrial function in keratinocytes and Schwann cells, and drove M1-to-M2 macrophage polarization via suppression of NF-κB signaling. In diabetic mice, treatment with mEVs@TAgel accelerated full-thickness wound closure, promoted re-epithelialization, angiogenesis, and collagen remodeling, and reduced scar formation through early Col 3 deposition and an improved Col 3/Col 1 ratio. Notably, in a sciatic nerve injury model, mEVs@TAgel enhanced functional recovery, axonal regeneration, remyelination, and muscle preservation. Long-term biosafety evaluations showed no systemic toxicity or inflammatory side effects. Altogether, mEVs@TAgel represents a safe and potent platform that coordinately mitigates oxidative stress, inflammation, and tissue damage, offering a promising strategy for diabetic wound and nerve repair.