Hybrid nanovesicles promote diabetic wound healing via dual-targeted multimodal therapy

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Nanotechnology

Background:

• Diabetic wounds suffer from persistent oxidative stress, chronic inflammation, and vascular dysfunction, creating a cycle of delayed healing.
• Existing therapies struggle to address these multifaceted challenges concurrently, leading to poor outcomes and high amputation rates.
• Developing novel therapeutic strategies is crucial for effective diabetic wound management.

Purpose of the Study:

• To engineer a biohybrid nanovesicle system (DFO@HEVs) for simultaneous targeting of oxidative stress, inflammation, and vascular dysfunction in diabetic wounds.
• To evaluate the therapeutic efficacy of DFO@HEVs in promoting diabetic wound healing both in vitro and in vivo.
• To investigate the underlying molecular mechanisms of DFO@HEVs in modulating cellular responses and tissue repair.

Main Methods:

• A biohybrid nanovesicle system (DFO@HEVs) was constructed by fusing endothelial and neutrophil-derived extracellular vesicles loaded with deferoxamine (DFO).
• Physicochemical properties, drug loading, and safety of DFO@HEVs were assessed.
• In vitro studies utilized high glucose/pro-oxidant-stimulated endothelial cells and macrophages, while in vivo studies employed diabetic mouse wound models.
• Analyses included microscopy, flow cytometry, histology, transcriptomics, and single-cell RNA sequencing.

Main Results:

• DFO@HEVs demonstrated dual targeting capabilities, enhancing endothelial cell uptake and homing to inflamed sites.
• Treatment promoted angiogenesis via PI3K/AKT/HIF-1α and VEGF pathways, reduced oxidative stress and ferroptosis via Nrf2 activation, and shifted macrophages to an anti-inflammatory M2 phenotype.
• In diabetic mice, DFO@HEVs significantly accelerated wound closure, re-epithelialization, and neovascularization while decreasing inflammation and oxidative damage.

Conclusions:

• DFO@HEVs represent a promising hybrid nanovesicle system for combined membrane and drug delivery, effectively addressing multiple barriers in diabetic wound healing.
• This approach disrupts the detrimental cycle of inflammation, ferroptosis, and impaired angiogenesis, creating a pro-healing microenvironment.
• DFO@HEVs show significant potential as a novel therapeutic strategy for chronic wound management.