CCR2-overexpressing mesenchymal stromal cell-derived extracellular vesicles loaded with MPA ameliorate lupus nephritis

Lupus nephritis (LN) is a common renal complication of systemic lupus erythematosus, and its severity is closely correlated with disease prognosis. Conventional therapy for LN faces challenges including multiple side-effects caused by systemic administration and low drug delivery efficiency due to lack of organ targeting. Herein, we designed a renal-targeted delivery platform based on C-C Motif Chemokine Receptor 2 (CCR2)-C-C Motif Chemokine ligand 2 chemotaxis, constructed by engineering CCR2-overexpressing mesenchymal stromal cell-derived EVs loaded with mycophenolic acid (MPA)-encapsulated MSNs (MPA@CMSNs). In LN models, MPA@CMSNs enabled efficient delivery of MPA into renal region and significantly alleviated kidney inflammation. Mechanistically, MPA@CMSNs effectively inhibited the proliferation and differentiation of proinflammatory immune cells, while concurrently suppressing the Dectin3/NF-κB signaling pathway in macrophages to remodel and optimize the renal immune microenvironment. Collectively, our findings present an efficient renal-targeted strategy with profound therapeutic efficacy against LN, offering a promising approach for targeted disease treatment.