摘要The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression.Peptide drugs,such as exenatide(Exe),with potential disease-modifying efficacy,have difficulty in crossing the blood-brain barrier(BBB)due to their large molecular weight.Herein,we fabricate multi-functionalized lipid nanoparticles(LNP)Lpc-BoSA/CSO with BBB targeting,permeability-increasing and responsive release functions.Borneol is chemically bonded with stearic acid and,as one of the components of Lpc-BoSA/CSO,is used to increase BBB permeability.Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma,and the amount is 4.21 times greater than that of conventional LNP.Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved,and the content of dopamine is 1.85 times(substantia nigra compacta)and 1.49 times(striatum)that of PD mice.α-Synuclein expression and Lewy bodies deposition are reduced to 51.85％and 44.72％of PD mice,respectively.Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41％.Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway,and effectively prevent the progressive deterioration of Parkinson's disease.In summary,Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.