A nasally administrated reactive oxygen species-responsive carrier-free gene delivery nanosystem for Alzheimer's disease combination therapy.

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.