A novel microneedle-based delivery of NRF2-overexpressing exosomes for scleroderma therapy.

Scleroderma is a chronic autoimmune connective tissue disease characterized by progressive skin fibrosis, vascular dysfunction, and immune dysregulation. Current therapies remain largely ineffective in reversing established fibrosis and are limited by systemic side effects. In this study, we developed a novel therapeutic strategy combining microneedle (MN)-mediated transdermal delivery with NRF2-overexpressing exosomes (NRF2-OE Exos) to locally enhance antioxidant, anti-fibrotic, anti-inflammatory, and pro-angiogenic effects in scleroderma. Exosomes were isolated from NRF2-OE adipose-derived stem cells (ADSCs) and incorporated into GelMA/PEGDA-based dissolvable MNs. These MNs demonstrated excellent mechanical strength, minimal invasiveness, sustained exosome release, and efficient cellular uptake in vitro. Functional assays showed that NRF2-OE Exos-loaded MNs significantly enhanced endothelial tube formation, preserved fibroblast mitochondrial integrity, and promoted macrophage polarization toward a reparative phenotype. In a bleomycin-induced murine scleroderma model, MN treatment reduced dermal thickening, collagen deposition, and α-SMA expression while promoting vascular regeneration and immunomodulation. Mechanistically, transcriptomic analysis revealed that NRF2-OE Exos suppressed pro-fibrotic Wnt and Hippo signaling pathways and activated calcium and cAMP signaling pathways. Moreover, NRF2-OE Exos alleviated mitochondrial dysfunction and ferroptotic injury by upregulating antioxidant and lipid peroxidation defense genes. Collectively, this study demonstrates that MN-mediated delivery of engineered exosomes offers a promising, localized, and multifaceted therapeutic approach for scleroderma, with strong translational potential.