Inhalable extracellular vesicle delivered IL-10 mRNA attenuates pulmonary hypertension in rats

Pulmonary hypertension is a lethal condition characterized by an enhanced inflammatory response in the lungs. Cytokines such as interleukin-10 (IL-10) have demonstrated considerable potential as potent inflammation suppressors. Especially, with pulmonary hypertension patients showing diminished IL-10 levels. However, off-target toxicity poses a major limitation to their applications. Here we report a strategy in which IL-10 mRNA, encapsulated in extracellular vesicles, is delivered by inhalation. Targeted delivery to lung with preferential uptake reduces systemic side effects. IL-10 mRNA exerts selective immunomodulatory effects by suppressing inflammatory cytokine secretion and promoting apoptosis in M1-like pulmonary macrophages while sparing M2-like macrophages. This macrophage subset-specific regulation reshapes the pulmonary cytokine microenvironment, significantly down-regulating factors that promote pulmonary hypertension progression and ultimately inhibiting disease progression. The strategy was demonstrated in the sugen5416/hypoxia-induced rat model of pulmonary hypertension, providing substantial protection against disease progression. This shows the potential for locally delivered cytokine-based immunosuppressive therapies for inflammatory lung diseases.