Membrane-Coated DNA Nanoflowers Attenuate Cognitive Decline in Apolipoprotein E4 Mice.

APOE4-driven mitochondrial dysfunction is one of the important primary drivers of cognitive decline in neurodegenerative diseases. However, achieving mitochondrial-targeted drug delivery in the nervous system requires overcoming multiple barriers, necessitating the development of a safer and more efficient bionanoparticle drug delivery system. DNA nanoflowers (DNFs), generated via rolling circle amplification (RCA), offer programmable platforms for creating targeted drug delivery vehicles. Here, we designed a multifunctional DNF surface conjugated with ferrocene groups, loaded with resveratrol, encoded with mitochondrial-targeting aptamers, and coated with neural stem cell membranes (DFRM). In vitro studies demonstrated that DFRM efficiently targeted neuronal mitochondria and mediated ROS-responsive drug release, ameliorating neuronal impairment through robust anti-inflammatory/antioxidant effects and enhanced mitochondrial biogenesis. Intranasal administration in model mice significantly improved cognitive and memory performance while attenuating key neurodegenerative hallmarks, including mitochondrial damage, blood-brain barrier leakage, and Aβ plaque deposition. The neural stem cell membrane coating enables brain entry and neuronal targeting via homing effects, ferrocene groups confer mitochondria-specific ROS-responsive release, and resveratrol provided therapeutic benefits through anti-inflammatory, antioxidant, and mitochondrial biogenesis-promoting actions. This integrated delivery system synergistically overcame multiple barriers to achieve precise targeting, offering a promising strategy for neurodegenerative disease therapy and prevention.