Abstract
Recently, oligonucleotide post-transcriptional gene silencing, antisense oligonucleotides, small interfering RNA, ribozymes, and Deoxyribozymes (DNAzymes) have been used to tackle neurodegenerative diseases such as Alzheimer's and polyglutamine diseases like Huntington's disease. However, the primary obstacle to the therapeutic effectiveness of these oligonucleotides is the blood-brain barrier (BBB), a crucial protective mechanism limiting drug penetration into brain cells. In this study, we generated a DNAzyme-loaded nanoliposome (DNZ-NLP) as a drug delivery system to effectively deliver and release the DNAzymes to the brain. The investigation of physicochemical characteristics of fabricated nanoliposomes, particularly size, morphology, and surface charge, revealed that the size of DNZ-NLPs was ~ 68 nm, an optimum size for brain delivery. Cellular uptake and cytocompatibility studies using SH-SY5Y human neuroblastoma cells demonstrated that both blank nanoliposomes (B-NLPs) and DNZ-NLPs were cytocompatible, and DNZ-NLPs had a stable biphasic release profile in 48 h. Most importantly, about 60% of intravenously administered DNZ-NLPs to the healthy mouse were found in the brains of the animals. These findings confirmed that DNZ-NLPs passed the BBB. The controlled release of DNAzymes, the maximal cytocompatibility, and significantly improved BBB permeability suggest that our DNZ-NLPs offer a promising formulation for delivering all types of oligonucleotides to the brain for neurodegenerative disease treatments.