Metal-Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid β Aggregation in Vivo

Recently, photooxygenation of amyloid β (Aβ) has emerged as an effective way to inhibit Aβ aggregation in Alzheimer's disease (AD) treatment. However, their further application has been highly obstructed by self-aggregation, no metal chelating ability, and poor protein-enrichment capacity. Herein, porphyrinic metal-organic frameworks (PMOFs) are utilized as a superior Cu^II chelating and photooxidation agent for inhibiting Aβ aggregation. We selected only four classical kinds of POMFs (Zr-MOF, Al-MOF, Ni-MOF, Hf-MOF) for further investigation in our study, which are stable in physiological conditions and exhibit excellent biocompatibility. Among them, Hf-MOF was the most efficient Aβ photooxidant. A possible explanation about the difference in capacity of ¹ O₂ generation of these four PMOFs has been provided according to the experimental results and DFT calculations. Furthermore, Hf-MOFs are modified with Aβ-targeting peptide, LPFFD. This can not only enhance Hf-MOFs targeting cellular Aβ to decrease Aβ-induced cytotoxicity, but also improve Aβ photooxidation in the complicated living environment. More intriguingly, in vivo studies indicate that the well-designed LPFFD modified Hf-MOFs can decrease Aβ-induced neurotoxicity and extend the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Our work may open a new avenue for using MOFs as neurotoxic-metal-chelating and photo-therapeutic agents for AD treatment.