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Article Abstract
Combination therapies targeting multiple pathways are needed in order to improve treatment outcomes in Alzheimer's disease (AD) due to its complex pathogenesis. Amyloid-β and microglia-mediated neuroinflammation significantly contribute to AD pathogenesis. Amyloid-β-related nucleic acid drugs have demonstrated considerable potential in AD treatment; however, their clinical translation is limited by complex synthesis processes and carrier toxicity. Herein, an intranasally administrated, reactive oxygen species (ROS)-responsive, carrier-free gene delivery nanosystem (FTBR-NAC) was constructed for re-polarizing microglia and decreasing amyloid-β expression. In this nanosystem, fingolimod was conjugated with biguanide via an ROS-responsive linker to form the carrier for β-secretase 1 siRNA (siBACE1) to form FTBR nanoparticles. The electropositivity of FTBR and mucolytic activity of N-acetylcysteine (NAC) together enhanced the brain entry of FTBR. Upon reaching the brain, FTBR responded to the elevated ROS at the pathological site, releasing siBACE1 and fingolimod. Administration of FTBR-NAC improved cognitive function in AD mice, demonstrating the high therapeutic efficacy of this relatively simple nanosystem.
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| http://dx.doi.org/10.1016/j.jconrel.2025.113604 | DOI Listing |
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