Functional Modification Of BP NSs For Inhibition Of Amyloid-β Protein Fibrillogenesis

The accumulation and aggregation of amyloid-β（Aβ）in the brain is one of the main pathological hallmark of Alzheimer’s disease（AD）.In addition,transition metal ions,especially Cu²⁺,can not only alter the aggregation pathway of Aβ,but also induce the production of reactive oxygen species（ROS）.Therefore,the development of a bifunctional inhibitor that can effectively inhibit Aβaggregation and selectively chelate Cu²⁺is a promising strategy for AD.The peptide inhibitor LK7（LVFFARK）,which our group designed previously,could inhibit Aβaggregation to a certain extent,but it had low solubility,was prone to self-aggregation,and had no function of chelating Cu²⁺,so it is necessary to modify it.Black phosphorous（BP）is a two-dimensional nanomaterial with high biocompatibility and unique biodegradability,and it could selectively chelate Cu²⁺.However,its application suffers from the rapid degradability and unfunctionability.To overcome the drawbacks of BP and LK7,we herein modified LK7 on the surface of BP and linked PEG to improve dispersibility of the nanosystem,and successfully synthesized PEG-LK7@BP.Various biochemical assays revealed that PEG-LK7@BP exhibited good stability and biocompatibility,and could significantly enhance the inhibitory effect on Aβaggregation.PEG-LK7@BP efficiently inhibited Aβ₄₂ fibrillogenesis,prevented the conformational transition of Aβ₄₂,reduced the cytotoxicity induced by Aβ₄₂,and increased cell viability from 72%to 100%.Furthermore,PEG-LK7@BP also had the ability to chelate Cu²⁺,so it not only inhibited Aβ₄₂ fibrillogenesis,but also regulated Cu²⁺-mediated Aβ₄₂ aggregation,indicating the characteristics of a bifunctional inhibitor.In addition,PEG-LK7@BP could potently prevent the production of ROS catalyzed by Cu²⁺or Cu²⁺-Aβ₄₂ complex.We designed and synthesized PEG-LK7@BP,which could effectively inhibit Aβ₄₂fibrillogenesis,regulate Cu²⁺-Aβ₄₂ complex aggregation and reduce the production of ROS.It is a bifunctional nano-inhibitor with potential application value,to provide new insights into the development of AD agents in the future.