Jian-Hong Li,1,2,* Jing Xu,1,2,* Chen Huang,1,2 Jin-Xia Hu,1,2 Hao-Ming Xu,1,2 Xue Guo,1,2 Yan Zhang,1,2 Jing-Kui Xu,1,2 Yao Peng,3 Yong Zhang,1,2 Min-Zheng Zhu,1,2 You-Lian Zhou,1,2 Yu-Qiang Nie1,2 

1Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China; 2Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China; 3Department of Gastroenterology and Hepatology, Shenzhen General Hospital, Shenzhen, People’s Republic of China

*These authors contributed equally to this work

Correspondence: You-Lian Zhou; Yu-Qiang Nie, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou, Guangdong, 510180, People’s Republic of China, Tel +86-155-2111-7161 ; +86-136-0904-5779, Email eyyoulianzhou@scut.edu.cn; eyynieyuqiang@scut.edu.cn

Background: Plant-derived exosome-like nanoparticles (PELNs) have received widespread attention in treating ulcerative colitis (UC). However, the role of Houttuynia cordata-derived exosome-like nanoparticles (HELNs) in UC remains unclear. This study aims to evaluate the efficacy of HELNs in treating colitis in mice and investigate its potential mechanisms.
Methods: HELNs were isolated from H. cordata for characterization, and their safety and stability were evaluated. A dextran sulfate sodium (DSS)-induced colitis mouse model was utilized to assess the therapeutic potential of HELNs in UC. In vivo, imaging and flow cytometry were utilized to investigate the targeting effect of HELNs on inflamed colonic sites and their modulation of the immune environment. RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by HELNs. Guided by transcriptomic findings, NLRP3−/− mice were used in conjunction with Western blotting, qPCR, immunofluorescence, and other techniques to verify that HELNs alleviated DSS-induced colitis by inhibiting NLRP3/NOD-like receptor signaling pathways. Lastly, the impact of HELNs on the gut microbiota was investigated through 16S rRNA sequencing.
Results: HELNs significantly reduced the severity of DSS-induced colitis in mice, alleviating colitis symptoms and histopathological damage. Furthermore, HELNs can specifically target inflamed colon tissue, regulate the immune environment, and decrease inflammation. RNA-seq analysis, coupled with the use of NLRP3−/− mice, demonstrated that HELNs inhibited the NLRP3/NOD-like receptor signaling pathways. Lastly, HELNs balanced the gut microbiota composition in mice with colitis, decreasing the abundance of harmful bacteria and increasing the abundance of beneficial bacteria in the intestinal tract of these mice.
Conclusion: In summary, HELNs exhibit the potential to protect the colon from DSS-induced damage by inhibiting the NLRP3/NOD-like receptor signaling pathway and modulating the gut microbiota, presenting a promising therapeutic option for the management of UC.

Keywords: Houttuynia-derived exosome-like nanoparticles, HELNs, NLRP3, gut microbiota, ulcerative colitis, UC