Blood–Brain Barrier-Crossing Photo-oxygenation Nanocomposite for the Selective Mapping and Disassembly of Amyloid-β Aggregates In Vivo

The accumulation of toxic amyloid-β (Aβ) aggregates in the brain underlies neuronal death and subsequent irreversible neurodegeneration in Alzheimer’s disease (AD). Currently, optimized theranostic probes targeting Aβ aggregates are still rare. Herein, we synthesized a series of tetraphenylethylene (TPE) derivatives for the selective recognition and photo-oxygenation of Aβ aggregates. Among them, TPE-yne-Indo with a strong electron-withdrawing group (benzo[e]indolium) and an electron-donating group (N,N-dimethylaniline) can selectively recognize Aβ aggregates in solution (K_d = 310.5 nM, S/N = 6.1) and mapping Aβ plaques in brain slices. Theoretical calculations indicated that TPE-yne-Indo engaged in hydrophobic interactions with the amino acid residues Val-18 (V), Ala-21 (A), and His-13 (H) of Aβ. Notably, the binding with Aβ aggregates bestowed TPE-yne-Indo with higher reactive oxygen species (ROS) generation ability, boosting the photodynamic oxidation of Aβ aggregates. Furthermore, therapeutic nanocomposite with the lactoferrin receptor ligand (MSN@Lf&TPE-yne-Indo) was prepared to facilitate the blood–brain barrier (BBB) crossing process. In vivo assays showed that MSN@Lf&TPE-yne-Indo can selectively stain Aβ plaques and reduce Aβ deposition in the brain of APP/PS1 mice, alleviating symptoms of cognitive impairment and memory loss. This study provides a promising tool for the early diagnosis and treatment of AD.