MiR-1290 in natural killer cell derived extracellular vesicles: a pathogenic mediator of lupus nephritis and therapeutic target for th17 regulation.

Lupus nephritis (LN), a severe organ manifestation of systemic lupus erythematosus (SLE), is primarily driven by an imbalance between pathogenic Th17 cells and regulatory T (Treg) cells. We found that NK cell-derived extracellular vesicles (NK-EVs) from LN patients, but not healthy controls, exhibited a distinct miRNA cargo that potently drives Th17 polarization. Small RNA sequencing identified miR-1290 as the most significantly upregulated miRNA in NK-EVs derived from LN patients. This finding was validated in an independent clinical cohort, where miR-1290 levels correlated with key disease activity indices. Functional analysis revealed that miR-1290 promoted Th17 differentiation and suppressed Treg generation by downregulating NR4A2. In the MRL/lpr lupus mice, systemic delivery of NK-EVs engineered to carry a miR-1290 antagomir restored the Th17/Treg balance, alleviated renal inflammation and fibrosis. Collectively, we found miR-1290 in NK-EVs disrupted T cell homeostasis by targeting NR4A2, driving Th17/Treg imbalance. Delivering miR-1290 antagomirs via engineered NK-EVs restored this balance and alleviated renal damage in LN mice.