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

Abstract 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 O 2 ) 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.