Alpha-synuclein (alpha-syn) deposition in Lewy bodies (LB) is one of the main neuropathological hallmarks of Parkinson's disease (PD). LB accumulation is considered a causative factor of PD, which suggests that strategies aimed at reducing alpha-syn levels could be relevant for its treatment. In the present study, we developed novel nanocarriers suitable for systemic delivery of small interfering ribonucleic acid (siRNA) that were specifically designed to reduce neuronal alpha-syn by RNA interference. Anionic liposomes loaded with an siRNA-protamine complex for alpha-syn gene silencing and decorated with a rabies virus glycoprotein (RVG)-derived peptide as a targeting agent were prepared. The nanoparticles were characterized for their ability to load, protect, and deliver the functional siRNA to mouse primary hippocampal and cortical neurons as well as their efficiency to induce gene silencing in these cells. Moreover, the nanocarriers were evaluated for their stability in serum. The RVG-decorated liposomes displayed suitable characteristics for future in vivo applications and successfully induced alpha-syn gene silencing in primary neurons without altering cell viability. Collectively, our results indicate that RVG-decorated liposomes may be an ideal tool for further studies aimed at achieving efficient in vivo alpha-syn gene silencing in mouse models of PD.