Photooxidative inhibition and decomposition of β-amyloid in Alzheimer's by nano-assemblies of transferrin and indocyanine green

Photoinduced modulation of Aβ42 aggregation has emerged as a therapeutic option for treating Alzheimer's disease (AD) due to its high spatiotemporal controllability, noninvasive nature, and low systemic toxicity. However, existing photo-oxidants have the poor affinity for Aβ42, low depolymerization efficiency, and difficulty in crossing the blood-brain barrier (BBB), hindering their application in the treatment of AD. Here, through hydrophobic interactions and hydrogen bonding, we integrated the near-infrared (NIR) photosensitizer indocyanine green with transferrin (denoted as TF-ICG), a protein with a high affinity for Aβ42, and demonstrated its anti-amyloid activity in vitro. TF-ICG was shown to bind to Aβ42 residues via hydrophobic interaction, impeding π-π stacking of Aβ42 peptide monomers and disassembling mature Aβ42 protofibrils in a concentration-dependent manner. More importantly, under NIR (808 nm, 0.6w/cm2) irradiation, TF-ICG completely inhibited the fibrillation process of Aβ42 to generate amorphous aggregates, with an inhibition rate of 96 % at only 65 nM. Meanwhile, TF-ICG could photo-oxidize rigid Aβ42 aggregates and break them down into small amorphous structures. Tyrosine fluorescence assay further demonstrated the intrinsic affinity and targeting of TF-ICG to Aβ42 fibrils. In vitro studies validated the anti-amyloid activity of TF-ICG, which provided a theoretical basis for further in vivo application as a BBB-penetrating nanotherapeutic platform.