Redox-responsive chitosan hydrogel releases mitochondria-targeted fullerenol to reprogram M1/M2 macrophage balance...

The M1/M2-macrophage imbalance that characterizes diabetic skin wounds sustains chronic inflammation, oxidative stress and bacterial colonization, thereby hindering healing. Although fullerenol [C₆₀(OH)_n]-loaded hydrogels (HGs) exert antioxidant properties that accelerate repair, a hydrogel system that specifically targets mitochondria to regulate macrophage polarization has not yet been reported. Here we synthesized a C₆₀(OH)_n-quaternized chitosan-carbomer hydrogel (C₆₀@QM-HG) utilizing quaternized chitosan modified with phenylboronic acid. C₆₀@QM-HG exhibited excellent injectability and water absorption capacity. Controlled release of C₆₀(OH)_n was achieved through reversible borate ester bonds, enabling tailored antioxidant effects under the conditions typical of diabetic wounds. C₆₀@QM-HG modulated mitochondrial redox responsive via the mitochondrial HSPA8-ROMO1 signaling axis to regulate M1/M2 polarization, resulting in significant antioxidant and anti-inflammatory effects. In summary, C₆₀@QM-HG improved the inflammatory microenvironment, accelerated re-epithelialization and collagen deposition, and enhanced healing of diabetic and infected wounds. To enhance mitochondrial targeting, C₆₀(OH)_n was conjugated with Apoptozole, an HSPA8 inhibitor, yielding AP&C₆₀@QM-HG, which further suppressed M1 polarization and promoted diabetic wound healing. This study provides new insights into anti-inflammatory and antimicrobial strategies for diabetic skin wounds through mitochondria-targeted regulation and controlled release of C₆₀(OH)_n.