Therapeutic Potential of Arginine‐Loaded Red Blood Cell Nanovesicles Targeting Obese Asthma

<b>Purpose:</b> The role of the gut microbiomes has been emphasized in the pathogenesis of obese asthma (OA). However, the molecular mechanism of airway dysfunction underlying OA has not yet been fully elucidated. The effects of microbiomes on arginine metabolism in relation to lung functions and a novel method for delivering arginine to lung tissue based on arginine-loaded red blood cell (RBC)-derived nanovesicles (NVs) (NV^Arg) will be investigated. <b>Materials and Methods:</b> Inflammatory status, amino acid profiles, and microbial diversity were evaluated in 20 adult patients with OA compared to 30 adult patients with non-OA (NOA) and 10 healthy control (HC) groups. Changes in gut or lung microbial composition that altered arginine metabolism in relation to airway inflammation were investigated in an OA mouse model in vivo. Additionally, this study evaluated the delivery of arginine to lung tissue utilizing NV^Arg in vivo and in vitro. <b>Results:</b> Significantly increased <i>Bacteroides</i> abundance but decreased serum arginine concentration with lower forced exhaled volume at 1 s (FEV₁) (%) was noted in the OA group compared to the NOA and HC groups. In mouse experiments, when OA mice were given living bacteria from normal control (NC) mice, lung arginine concentration and airway resistance were restored. However, the administration of arginine or its metabolite (citrulline) did not increase the arginine levels in the lung tissues. We therefore created NV^Arg, which successfully delivered arginine into the cytoplasm of the airway epithelial cell line <i>in vitro</i>. Oral administration of NV^Arg for OA mice significantly induced the AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) pathways in airway epithelial cells, which reduced airway resistance and inflammation. <b>Conclusion:</b> These findings suggest that microbiomes contribute to airway dysfunction by regulating arginine metabolism, whereas NV^Arg treatment may be a potential option for managing OA.