Houttuynia cordata-derived exosome-like nanovesicles attenuate acute lung injury with concomitant changes in CXCL10 and p38 MAPK/ATF2 signaling.

Acute lung injury (ALI) is a life-threatening respiratory condition with limited therapeutic options, requiring safer and more effective therapeutic strategies. This study aims to investigate the potential of Houttuynia cordata-derived exosome-like nanovesicles (HcNVs) as a novel therapeutic approach for lipopolysaccharide (LPS)-induced ALI. HcNVs were isolated using tangential flow filtration and were characterized. Oral administration of HcNVs significantly alleviated ALI, as evidenced by reduced histopathological damage, pulmonary edema, vascular permeability, and pro-inflammatory cytokine production. Flow cytometry and immunofluorescence analyses demonstrated decreased infiltration of immune cells in lung tissue. From a correlational perspective, HcNVs treatment is associated with reduced activity of the p38 MAPK/ATF2 signaling pathway, accompanied by downregulation of CXCL10 expression and decreased inflammatory cell recruitment. In vitro, HcNVs suppressed LPS-induced inflammatory responses and apoptosis in RAW264.7 and MH-S macrophages. In addition, 16S rRNA sequencing results showed that HcNVs treatment was associated with an increase in gut microbial diversity and a decrease in the abundance of inflammation-related microbiota, which may be related to the regulation of the gut-lung axis. Importantly, biosafety assessments confirmed the excellent biocompatibility of HcNVs in both cell and animal models. These findings highlight the therapeutic potential of HcNVs as a natural, safe, and effective nanoplatform for treating inflammatory lung diseases and support their further development for clinical translation.