Near-Infrared Photothermally Enhanced Photo-Oxygenation for Inhibition of Amyloid-beta Aggregation Based on RVG-Conjugated Porphyrinic Metal-Organic Framework and Indocyanine Green Nanoplatform

Amyloid aggregation is associated with many neurodegenerative diseases such as Alzheimer's disease (AD). The current technologies using phototherapy for amyloid inhibition are usually photodynamic approaches based on evidence that reactive oxygen species can inhibit A beta aggregation. Herein, we report a novel combinational photothermally assisted photo-oxygenation treatment based on a nano-platform of the brain-targeting peptide RVG conjugated with the 2D porphyrinic PCN-222 metal-organic framework and indocyanine green (PCN-222@ICG@RVG) with enhanced photo-inhibition in Alzheimer's A beta aggregation. A photothermally assisted photo-oxygenation treatment based on PCN@ICG could largely enhance the photo-inhibition effect on A beta(42) aggregation and lead to much lower neurotoxicity upon near-infrared (NIR) irradiation at 808 nm compared with a single modality of photo-treatment in both cell-free and in vitro experiments. Generally, local photothermal heat increases the instability of A beta aggregates and keeps A beta in the status of monomers, which facilitates the photo-oxygenation process of generating oxidized A beta monomers with low aggregation capability. In addition, combined with the brain-targeting peptide RVG, the PCN-222@ICG@RVG nanoprobe shows high permeability of the human blood-brain barrier (BBB) on a human brain-on-achip platform. The ex vivo study also demonstrates that NIR-activated PCN-222@ICG@RVG could efficiently dissemble A beta plaques. Our work suggests that the combination of photothermal treatment with photo-oxygenation can synergistically enhance the inhibition of A beta aggregation, which may boost NIR-based combinational phototherapy of AD in the future.