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 has 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) nano delivery 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 pathological spleen and efficiently deliver miR-125a into the splenic T cells in SLE mice model. 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.