Redox Oxygen Species‐Responsive Nanotheranostics with Dual‐Channel Fluorescent Turn‐On for Early Diagnosis and Targeted Therapy of Alzheimer's Disease

Abstract Current diagnosis and treatment strategies mainly focus on the pathologies of the mid‐to‐late stage of AD (Alzheimer's disease), with clinical outcomes that are far from ideal. Herein, we developed the ROS (reactive oxygen species)‐responsive brain neuronal targeting nanotheranostic platforms that possess the dual‐channel fluorescent “turn‐on” properties and release drugs in AD neurons in response to ROS, thereby simultaneously facilitating the diagnosis and therapy of early AD. Through the modification of acetylcholine receptor targeting RVG29 peptide, the nanotheranostics penetrated BBB and accumulated into diseased neurons in an intact form, consequently maximizing the diagnostic and therapeutic performance. The anti‐oxidative drug baicalein conjugated onto the surface of nanotheranostics via ROS‐cleavable boronate ester linkage rapidly released for ROS scavenging, while the encapsulated fluorophores turned on their fluorescence for AD diagnosis upon microenvironment stimuli. This nanotheranostic strategy exhibited highly sensitivity with a ROS detection limit of up to 100 µ m and accurately early detection of ROS in 3×Tg AD mice at 6 months of age in vivo. In addition, it could also rescue memory defects, scavenge oxidative stress, attenuate neuroinflammation and enhance neuroprotective effect in 3×Tg AD mice. This work opens up a promising and smart strategy for early diagnosis and therapy in neurodegenerative disease.