RATIONALE: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene play an important role in Parkinson's disease (PD) pathogenesis, and downregulation of LRRK2 has become a promising therapy for PD. Here, we developed a synthetic biology strategy for the self-assembly and delivery of small interfering RNAs (siRNAs) of LRRK2 into the substantia nigra via small extracellular vesicles (sEVs) using a genetic circuit (in the form of naked DNA plasmid) to attenuate PD-like phenotypes in mouse model. METHODS: We generated the genetic circuit encoding both a neuron-targeting rabies virus glycoprotein (RVG) tag and a LRRK2 siRNA under the control of a cytomegalovirus (CMV) promoter, and assessed its therapeutic effects using LRRK2 RESULTS: After intravenous injection, the genetic circuit was taken up by the host liver to reprogram liver cells to produce and self-assemble LRRK2 siRNAs into sEVs, and then the sEV-enclosed LRRK2 siRNAs were further transferred by the endogenous circulating system of sEVs and guided by the RVG tag to the substantia nigra. Intravenous injection of this genetic circuit reduced total and phosphorylated LRRK2 levels in the substantia nigra, and attenuated PD-like phenotypes in two mouse models by rescuing LRRK2 CONCLUSION: This study provides an efficient therapeutic strategy to attenuate LRRK2-induced neurodegeneration and neuroinflammation in PD mouse models, and may open a new avenue to safely deliver siRNA into brain after peripheral intravenous injection and facilitate PD treatment.