Multifunctional near-infrared fluorescent probe for imaging of hydrogen peroxide and photodynamic therapy of amyloid-β aggregation in Alzheimer's disease.

Photodynamic therapy (PDT) has shown significant potential in eliminating amyloid-β (Aβ) aggregates, the characteristic pathological marker of Alzheimer's disease (AD). However, traditional photosensitizers have limitations such as off-target oxidation and single functionality, which severely hinder their specificity and therapeutic efficiency in clearing Aβ plaques. Given the complexity of AD's pathological mechanisms, the development of novel photosensitizers with both targeting ability and multifunctionality has become an urgent priority. In this study, a H2O2-responsive near-infrared (NIR) fluorescent probe ENBS-P was designed and synthesized. By integrating the dual functions of H2O2 visualization and precise photodynamic therapy, it has achieved efficient application in both in vitro and in vivo models. ENBS-P could be specifically activated by H2O2 to release ENBS, resulting in a significant enhancement of fluorescence signal at 720 nm (λex = 640 nm), thus realizing highly sensitive in situ detection of H2O2 (LOD = 0.2 μM). In addition, benefiting from a more efficient intersystem crossing (ISC) process from S1 to T1, the therapeutic molecule ENBS, generated after the specific activation of ENBS-P by H2O2, could produce superoxide radical anions (O2-•, Type I photoreaction) under NIR light excitation. Importantly, through imaging-guided PDT, it could effectively inhibit the aberrant aggregation of Aβ42 and promote the dissociation of formed aggregates. This study overcomes the limitations of traditional photosensitizers by providing an innovative "diagnosis-treatment" integrated strategy for the early diagnosis and therapy of AD, holding significant promise for advancing precision medicine in AD.