Ultrasensitive Electrochemical Detection of Amyloid-β Peptide Using a Homochiral Metal–Organic Framework Binding to the <scp>l</scp> -Diphenylalanine Targeting Site

The high sensitivity and accuracy of amyloid-β peptide (Aβ) detection could provide strong support for early diagnosis, monitoring of disease progression, and effective treatment of Alzheimer's disease (AD). Improving the specificity and affinity of sensing materials for Aβ is key to detecting Aβ. Herein, an electrochemical sensor based on an unmodified homochiral MOF, <b>Zn-BPIleBp</b>, was developed for the first time for the detection of Aβ1-40, with an ultralow detection limit of 1.7 pM (7.36 pg/mL). The <b>Zn-BPIleBp</b> sensor also displays high-efficiency enantioselectivity and ultrasensitivity in identifying diphenylalanine (PhePhe) corresponding to the core recognition motif of Aβ1-40, with a high peak current ratio (<i>I</i>_L/<i>I</i>_D) of 2.78, large potential difference (<i>E</i>_L - <i>E</i>_D) of 140 mV, and ultralow detection limit of 34 fM for l-PhePhe. The sensor has been successfully applied for the ultrasensitive quantification of l-PhePhe and Aβ1-40 in racemic mixtures, artificial cerebrospinal fluid (aCSF) and fetal bovine serum (FBS). According to structural and spectral analysis, the high sensitivity and affinity of homochiral MOF toward Aβ1-40, without the involvement of any biomolecular modifications such as antibodies or aptamers, stem from the structural, hydrophobic, and chiral matching between the framework and Aβ1-40. This sensor proffers a fast, highly stable, reproducible, ultrasensitive, and accurate detection method for Aβ1-40, demonstrating great potential in the clinical application of AD. This work also opens up new perspectives for designing sensing platforms using MOFs as sensing materials and expanding their functionality and applications to the fields of biological and medical analysis.