An in situ-activated and chemi-excited photooxygenation system based on G-poly(thioacetal) for Aβ_1-42 aggregates

The abnormal aggregation of Aβ proteins, inflammatory responses, and mitochondrial dysfunction have been reported as major targets in Alzheimer's disease (AD). Photooxygenation of the amyloid-β peptide (Aβ) is viewed as a promising therapeutic intervention for AD treatment. However, the limitations of the depth of the external light source passing through the brain and the toxic side effects on healthy tissues are two significant challenges in the photooxidation of Aβ aggregates. We proposed a method to initiate the chemical stimulation of Aβ_1-42 aggregate oxidation through H₂O₂ and correct the abnormal microenvironment of the lesions by eliminating the cascading reactions of oxidative stress. The degradable G-poly(thioacetal) undergoes cascade release of cinnamaldehyde (CA) and thioacetal triggered by endogenous H₂O₂, with CA in turn amplifying degradation by generating more H₂O₂ through mitochondrial dysfunction. A series of novel photosensitizers have been prepared and synthesized for use in the photodynamic oxidation of Aβ_1-42 aggregates under white light activation. The nanoparticles (BD-6-QM/NPs) self-assembled from BD-6-QM, bis[2,4,5-trichloro-6-(pentoxycarbonyl) phenyl] ester (CPPO), and G-poly(thioacetal) not only exhibit H₂O₂-stimulated controlled release but also can be chemically triggered by H₂O₂ to generate singlet oxygen to inhibit Aβ_1-42 aggregates, reducing the Aβ_1-42-induced neurotoxicity.