Systemic lupus erythematosus (SLE), a common lethal autoimmune disease, is characterized by effector/regulatory T cells imbalance. Current therapies are either inefficient or have severe side effects. MicroRNA-125a (miR-125a) can stabilize Treg-mediated self-tolerance by targeting effector programs, but it is significantly downregulated in peripheral T cells of patients with SLE. Therefore, overexpression of miR-125a may have therapeutic potential to treat SLE. Considering the stability and targeted delivery of miRNA remains a major challenge in vivo, we constructed a monomethoxy (polyethylene glycol)-poly­(d,l-lactide-co-glycolide)-poly­(l-lysine) (mPEG-PLGA-PLL) nanodelivery system to deliver miR-125a into splenic T cells. Results demonstrate that miR-125a-loaded mPEG-PLGA-PLL (PEALmiR‑125a) nanoparticles (NPs) exhibit good biocompatibility and protect miR-125a from degradation, thereby prolonging the circulatory time of miRNA in vivo. In addition, PEALmiR‑125a NPs are preferentially enriched in a pathological spleen and efficiently deliver miR-125a into the splenic T cells in SLE mice models. The PEALmiR‑125a NPs treatment significantly alleviates SLE disease progression by reversing the imbalance of effector/regulatory T cells. Collectively, the PEALmiR‑125a NPs show excellent therapeutic efficacy and safety, which may provide an effective treatment for SLE.

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