Design of aggregation-induced emission-active fluorogen-based nanoparticles for imaging and scavenging Alzheimer's β-amyloid by photo-oxygenation

Abstract

Photo-oxygenation has emerged as an effective modality for scavenging Alzheimer's amyloid-β (Aβ) plaques. However, limitations of the current photo-oxidants, such as low Aβ-targeting and single functionality, hinder the scavenging of Aβ plaques via photo-oxygenation. Herein, based on an aggregation-induced emission (AIE)-active fluorogen (named TPMD), we designed AIE photo-oxidant nanoparticles (T-LD NPs) for Aβ imaging, inhibition, and disaggregation. The T-LD NPs were prepared by the assembly of hydrophobic TPMD with an Aβ-targeting peptide (LPPFD, L) conjugated amphiphilic polymer (DSPE-PEG). Such T-LD NPs could specifically label Aβ plaques for image-guided therapy. Under laser irradiation, T-LD NPs generated a plethora of reactive oxygen species (ROS), including ¹O₂, ˙OH, and O₂˙⁻, to oxygenate Aβ species, leading to the potent inhibition of Aβ fibrillization, and significant alleviation of Aβ-mediated neurotoxicity (36% to 10% at 20 μg mL⁻¹). Notably, T-LD NPs could rapidly disaggregate mature Aβ fibrils into fractured β-sheet rich aggregates via photo-oxygenation, resulting in alleviated cytotoxicity. In vivo studies revealed that the photo-activated T-LD NPs scavenged amyloid plaques in the transgenic C. elegans strain CL2006 and extended the lifespan by 4 days. Taken together, this multifunctional T-LD NP integrated Aβ-targeting, near-infrared fluorescence imaging, and photo-oxygenation, provides a new strategy for the development of multifunctional AIE photo-oxidants for the treatment of Alzheimer's disease.