Due to the composed alpha-helical/beta-strand structures, beta-amyloid peptide (A beta) is sensitive to chiral environments. The orientation and chirality of the Afi strand strongly influence its aggregation. A beta-formed fibrils have a cascade of chirality. Therefore, for selectively targeting amyloid aggregates, chirality preference can be one key issue. Inspired by the natural stereoselectivity and the beta-sheet structure, herein, we synthesized a series of D- and L-amino acid-modified polyoxometalate (POM) derivatives, including positively charged amino acids (D-His and L-His) and negatively charged (D-Glu and L-Glu) and hydrophobic amino acids (D-Leu, L-Leu, D-Phe, and L-Phe), to modulate A beta aggregation. Intriguingly, Phe-modified POMs showed a stronger inhibition effect than other amino acid- modified POMs, as evidenced by multiple biophysical and spectral assays, including fluorescence, circular dichroism, NMR, molecular dynamic simulations, and isothermal titration calorimetry. More importantly, D-Phe-modified POM had an 8-fold stronger inhibition effect than L-Phe-modified POM, indicating high enantioselectivity. Furthermore, in vivo studies demonstrated that the chiral POM derivatives crossed the blood-brain barrier, extended the life span of AD transgenic Caenorhabditis elegans CL2006 strain, and had low cytotoxicity, even at a high dosage.