An Antisense Oligonucleotide-Loaded Blood–Brain Barrier Penetrable Nanoparticle Mediating Recruitment of Endogenous Neural Stem Cells for the Treatment of Parkinson’s Disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic (DA) neurons and currently cannot be cured. One selected antisense oligonucleotide (ASO) is reported to be effective for the treatment of PD. However, ASO is usually intrathecally administered by lumbar puncture into the cerebral spinal fluid, through which the risks of highly invasive neurosurgery are the major concerns. In this study, ZAAM, an ASO-loaded, aptamer Apt 19S-conjugated, neural stem cell membrane (NSCM)-coated nanoparticle (NP), was developed for the targeted treatment of PD. NSCM facilitated the blood-brain barrier (BBB) penetration of NPs, and both NSCM and Apt 19S promoted the recruitment of the neural stem cells (NSCs) toward the PD site for DA neuron regeneration. The behavioral tests demonstrated that ZAAM highly improved the efficacy of ASO on PD by the targeted delivery of ASO and the recruitment of NSCs. This work is a heuristic report of (1) nonchemoattractant induced endogenous NSC recruitment, (2) NSCM-coated nanoparticles for the treatment of neurodegenerative diseases, and (3) systemic delivery of ASO for the treatment of PD. These findings provide insights into the development of biomimetic BBB penetrable drug carriers for precise diagnosis and therapy of central nervous system diseases.