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

作者：Mingguang Zhu, Jiahao Han, Ran Liu, Chaofeng Zhu, Fanghui Liang, Guoyang Zhang, Lijun Ma, Yulong Jin, Suying Xu, Zhuo Wang · 发表于：ACS Applied Materials & Interfaces · 年份：2025 · DOI：10.1021/acsami.5c11173 · 被引用次数：3 · 研究领域：Alzheimer's disease research and treatments、Supramolecular Self-Assembly in Materials、Advanced Drug Delivery Systems

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.