Aβ-Targeted Theranostic Agent for NIR Fluorescence Imaging Guided Type-I and Type-II Dual Photodynamic Therapy of Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of β-amyloid (Aβ), a key contributor to its pathogenesis. Current diagnostic and therapeutic strategies are hindered by limitations such as low sensitivity, high costs, limited efficacy, and severe side effects. In this study, we rationally designed a series of novel theranostic agents integrating Aβ-targeted fluorescence imaging and photodynamic therapy (PDT). Following theoretical calculations and experimental validation, we identified TA-2 as a promising candidate with superior binding affinity, excellent specificity, and a significant NIR fluorescence response to Aβ conformers. Upon NIR light activation, TA-2 generated both O₂^•- and ¹O₂ via Type I and II dual mechanisms. This dual ROS generation profile is particularly beneficial for addressing the hypoxic conditions often encountered in Alzheimer's disease (AD) pathology. The photoinduced ROS specifically oxidized critical Aβ residues, disrupting Aβ aggregation and disassembling preformed Aβ fibrils. In vitro, TA-2 demonstrated neuroprotection against Aβ-induced cytotoxicity by alleviating neuronal apoptosis. Following systemic administration, TA-2 easily crossed the blood-brain barrier, bound specifically to Aβ plaques, and enabled real-time monitoring of AD progression and therapeutic efficacy via NIR fluorescence imaging. Meanwhile, PDT with TA-2 resulted in a reduction of cerebral Aβ burden, leading to improved cognitive function in AD mice. These findings position TA-2 as a promising Aβ-targeted theranostic agent, combining both fluorescence imaging and spatiotemporally controlled PDT for AD diagnosis and treatment. This work demonstrates a new paradigm of NIR fluorescence imaging guided PDT for precise AD intervention.