Pueraria lobata-derived exosome-like nanovesicles alleviate rheumatoid arthritis via targeting Ruminococcus gnavus phenylethylamine production.

Gut microbiota has been widely recognised as playing a critical role in maintaining immune imbalance and the development of rheumatoid arthritis (RA). As key roles mediating interkingdom crosstalk among plants, microbiomes and mammals, plant-derived exosome-like nanoparticles (ELNs) could use lipids and microRNA components to precisely modulate gene expression of gut microbiota, showing potential as a dietary intervention for RA treatment. We aimed to investigate gut microbiota-immune interactions inducing immune dysregulation in RA and explore potential applications of edible plant-derived ELNs for RA treatment through gut microbiota manipulation. Combinations of microbial analysis of clinical cohort, metabolomics, in vivo and in vitro examination were performed to establish potential gut-immune mechanisms for interventions. Several representative edible plants ELNs were chosen to compare the modulation effects based on the above mechanism. Small RNA sequencing and lipidomic analysis were performed to identify key components and reveal the related mechanisms mediating therapeutic effects. Ruminococcus gnavus was significantly enriched in RA and aggravated arthritis through secreting phenylethylamine (PEA) to induce excessive neutrophil extracellular traps (NETs) formation. Among several plants ELNs, Pueraria lobata-derived ELNs (Pu-ELNs) were preferentially taken up by R. gnavus and decreased PEA production. Mechanistically, the lipid components of Pu-ELNs induced intestinal accumulation of ELN-derived gma-miR4412, which reduces phenylalanine decarboxylase (PDC) expression, relieving the arthritis aggravation caused by R. gnavus through acting on the PEA-Bruton's tyrosine kinase (BTK)-NETs axis. Our findings suggest the crucial role of R. gnavus in aggravating RA and underscore the application of plant-derived ELNs for microbiota manipulation.