Specialized Pro-Resolving Mediator loaded Extracellular Vesicles Mitigate Pulmonary Inflammation.

Area of Science:

• Biomedical Engineering
• Inflammation Research
• Drug Delivery Systems

Background:

• Specialized pro-resolving mediators (SPMs) actively resolve inflammation but are often at low in vivo levels.
• SPMs like resolvins are synthesized via transcellular and aspirin-triggered pathways involving lipoxygenases and cyclooxygenase-2 (COX-2).

Purpose of the Study:

• To engineer a cell-based platform for enhanced SPM synthesis and delivery.
• To investigate the therapeutic potential of Resolvin-loaded extracellular vesicles (EVs) in inflammatory conditions.

Main Methods:

• Constructed a multigene vector co-expressing COX-2, 5-lipoxygenase (5-LOX), and 15-lipoxygenase (15-LOX).
• Transfected HEK293T cells to produce resolvins from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), packaging them into EVs.
• Evaluated EV efficacy in vitro (neutrophil adhesion, barrier integrity, NF-κB activity, efferocytosis) and in vivo (pulmonary inflammation in LPS-treated mice).

Main Results:

• Engineered cells successfully produced resolvins via transcellular and aspirin-triggered pathways.
• Resolvin-loaded EVs inhibited neutrophil adhesion, preserved endothelial barrier function, suppressed inflammation markers, and enhanced efferocytosis in vitro.
• EV administration mitigated pulmonary inflammation in mice without significant toxicity.

Conclusions:

• A novel cell-based platform for generating Resolvin-loaded EVs was successfully developed.
• These EVs demonstrate significant potential for mitigating acute pulmonary inflammation.
• The platform offers a promising strategy for treating various inflammatory diseases.