This study investigates the genotoxicity of mercaptoacetic acid-coated CdSe-core quantum dots (MAA-QDs) and explores the underlying mechanisms. Using a plasmid-based system, the researchers detected changes in DNA configuration and biological activities to assess the genotoxic effects of MAA-QDs. The results showed that MAA-QDs significantly enhanced the conversion of covalently closed circular (CCC) DNA to open circular (OC) DNA and decreased the residual transformation activity of plasmid DNA, indicating concentration-dependent DNA damage. Electrospray ionization mass spectrometry data suggested that the genotoxicity might be correlated with the formation of the cadmium-mercaptoacetic acid complex (Cd–MAA). Circular dichroism spectroscopy and transformation assays indicated that the Cd–MAA complex interacted with DNA through a groove-binding mode, preferentially binding to DNA fragments with high adenine and thymine content. The study concludes that the Cd–MAA complex in MAA-QDs contributes to DNA damage and reduces the biological activity of DNA, highlighting the need for further research and safety measures in the use of quantum dots in biological applications.This study investigates the genotoxicity of mercaptoacetic acid-coated CdSe-core quantum dots (MAA-QDs) and explores the underlying mechanisms. Using a plasmid-based system, the researchers detected changes in DNA configuration and biological activities to assess the genotoxic effects of MAA-QDs. The results showed that MAA-QDs significantly enhanced the conversion of covalently closed circular (CCC) DNA to open circular (OC) DNA and decreased the residual transformation activity of plasmid DNA, indicating concentration-dependent DNA damage. Electrospray ionization mass spectrometry data suggested that the genotoxicity might be correlated with the formation of the cadmium-mercaptoacetic acid complex (Cd–MAA). Circular dichroism spectroscopy and transformation assays indicated that the Cd–MAA complex interacted with DNA through a groove-binding mode, preferentially binding to DNA fragments with high adenine and thymine content. The study concludes that the Cd–MAA complex in MAA-QDs contributes to DNA damage and reduces the biological activity of DNA, highlighting the need for further research and safety measures in the use of quantum dots in biological applications.