Nanometer-scale chirality has gained significant interest from different research fields due to its fundamental importance in nature and living matter. In this study, we design and synthesize chiral penicillamine-capped selenium nanoparticles (L-/D-Pen@Se NPs) that can act as a novel class of chiral amyloid-beta (A beta) inhibitors. In this work, D-Pen@Se NPs demonstrate higher inhibition efficiency, as well as ameliorate cognition and memory impairments. We used rat pheochromocytoma (PC12) cells to perform real-time cell analysis assay (RTCA) to probe the potential cytotoxicity of L-/D-Pen@Se NPs. At any given time point, the cell index decreases as o-Pen@Se NPs concentration increases, demonstrating a concentration-dependent cytotoxic effect on PC12 cells. In addition, o-Pen@Se NPs also reduced Zn2+-induced intracellular A beta(40) fibrillation, while L-Pen@Se NPs did not. The histological analysis demonstrates that mice treated with D-Pen@Se NPs did not exhibit signs of in vivo systemic toxicity in major organs. Our findings are highly encouraging in terms of providing substantial evidence of the safety of chiral D-Pen@Se NPs for biomedical application. We expect that these results will be relevant for other chiral NPs for treatment of Alzheimer's disease and have broad implications in NP-based studies and applications. (C) 2017 Elsevier Inc. All rights reserved.