Chirality of Copper–Amino Acid Nanoparticles Determines Chemodynamic Cancer Therapeutic Outcome

Abstract Chirality is a prevalent characteristic in nature, where biological systems exhibit a significant preference for specific enantiomers of biomolecules. However, there is a limited exploration into utilizing nanomaterials’ chirality to modulate their interactions with intracellular substances. In this study, self‐assembled copper‐cysteine chiral nanoparticles and explore the influence of their charity on cancer chemodynamic therapy (CDT) are fabricated. Experimental and molecular dynamics (MD) simulation results demonstrate that the copper‐l‐cysteine chiral nanoparticles (Cu‐l‐Cys NPs) exhibit a stronger affinity toward l‐glutathione (l‐GSH) that is overproduced in cancer cells, compared to the copper‐d‐cysteine enantiomer (Cu‐d‐Cys NPs). The interaction between Cu‐l‐Cys NPs and l‐GSH triggers a redox reaction that depletes l‐GSH and converts Cu2+ into Cu+. Subsequently, Cu+ catalyzes a Fenton‐like reaction, decomposing H2O2 into highly cytotoxic hydroxyl radicals (•OH) for cancer CDT. In vivo, results confirm that Cu‐l‐Cys NPs with good biocompatibility elicit a pronounced cancer cell death and effectively inhibit tumor growth. This work proposes a new perspective on chirality‐enhanced cancer therapy.