Background: Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by substantial loss of neurons in the substantia nigra pars compacta and depletion of dopamine. Cognitive impairment is one of the primary non-motor symptoms in PD patients. It has been reported that cordycepin (Cor) can alleviate cognitive impairment in neurodegenerative diseases, but it is susceptible to degradation by adenosine deaminase (ADA). This study aims to synthesize Cordycepin-Nano-Particles (CNP) which has resistance to ADA enzyme degradation, and investigate the effects of CNP on PD hippocampal slice models. Methods: Cor was chemically coupled with mPEG and mPEG-biotin to prepare CNP. CNP were determined using infrared spectroscopy, particle size measurement, and transmission electron microscopy. Extracellular electrophysiological recordings were used to record the field excitatory postsynaptic potential (fEPSP) in Schaffer-CA1 pathway of hippocampal slices in mice. An in vitro PD brain slice model was established with 1-methyl-4-phenylpyridinium (MPP+). Results: The proposed CNP was a spherical surface morphology, with an average particle size of about 220 nm. CNP resist the ADA enzyme degradation, exhibit higher viability in HT22 cells compared to Cor, and significantly alleviate cell damage induced by MPP+. CNP enhanced synaptic transmission in the Schaffer-CA1 pathway of hippocampal slices through A2AR pathway, reduced the excitability and tissue activity induced by 40 μM MPP+. Conclusion: CNP was successfully prepared with higher safety compared to Cor, and can protect Cor from ADA degradation. CNP primarily enhances synaptic transmission in mouse hippocampal slices through the adenosine A2AR pathway and reduces the excitability induced by MPP+.