NIR-II Hydrogen-Bonded Organic Frameworks (HOFs) Used for Target-Specific Amyloid-β Photooxygenation in an Alzheimer's Disease Model

Phototherapy has emerged as a powerful approach for interrupting β-amyloid (Aβ) self-assembly. However, deeper tissue penetration and safer photosensitizers are urgent to be exploited for avoiding damaging nearby normal tissues and improving therapeutic effectiveness. A hydrogen-bonded organic framework (HOF)-based NIR-II photooxygenation catalyst is presented here to settle the abovementioned challenges. By encapsulating the pyridinium hemicyanine dye DSM with a large two-photon absorption (TPA) cross-section in NIR-II window into the porphyrin-based HOF, the resultant DSM@n-HOF-6 exhibits significant two-photon NIR-II-excited Fluorescence Resonance Energy Transfer (FRET) to generate singlet oxygen (¹ O₂ ) for Aβ oxidation. Further, the target peptides of KLVFFAED (KD8) are covalently grafted on DSM@n-HOF-6 to enhance the blood-brain barrier (BBB) permeability and Aβ selectivity. The HOF-based photooxygenation catalyst shows an outstanding inhibitory effect of Aβ aggregation upon the NIR-II irradiation. Further in vivo studies demonstrate the obvious decrease of craniocerebral Aβ plaques and recovery of memory deficits in triple-transgenic AD (3×Tg-AD) model mice.