Chiral cysteine-copper ion-based assemblies for improved phototherapy

Phototherapy, encompassing photothermal therapy and photodynamic therapy, is gaining attention as an appealing cancer treatment modality. To enhance its clinical implementation, a comprehensive exploration of the pivotal factors influencing phototherapy is warranted. In this study, the L/D-cysteine (Cys)-copper ion (Cu2+) chiral nanoparticles, through the assembly of L/D-Cys-Cu2+ coordination complexes, were constructed. We found that these nanoparticles interacted with chiral liposomes in a chirality-dependent manner, with D-Cys-Cu2+ nanoparticles exhibiting more than three times stronger binding affinity than L-Cys-Cu2+ nanoparticles. Furthermore, we demonstrated that the D-Cys-Cu2+ nanoparticles were more efficiently internalized by Hela cells in contrast with L-Cys-Cu2+. On this basis, indocyanine green (ICG), acting as both photothermal and photodynamic agent, was encapsulated into L/D-Cys-Cu2+ nanoparticles. Experimental results showed that the L-CysCu2+-ICG and D-Cys-Cu2+-ICG nanoparticles displayed almost identical photothermal performance and singlet oxygen (1O2) generation capability in aqueous solution. However, upon laser irradiation, the D-Cys-Cu2+-ICG nanoparticles achieved enhanced anti-tumor effects compared to L-Cys-Cu2+-ICG due to their chirality-promoted higher cellular uptake efficiency. These findings highlight the crucial role of chirality in phototherapy and provide new perspectives for engineering cancer therapeutic agents.