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 (Cu) chiral nanoparticles, through the assembly of L/d-Cys-Cu coordination complexes, were constructed. We found that these nanoparticles interacted with chiral liposomes in a chirality-dependent manner, with d-Cys-Cu nanoparticles exhibiting more than three times stronger binding affinity than l-Cys-Cu nanoparticles. Furthermore, we demonstrated that the d-Cys-Cu nanoparticles were more efficiently internalized by Hela cells in contrast with l-Cys-Cu. On this basis, indocyanine green (ICG), acting as both photothermal and photodynamic agent, was encapsulated into L/d-Cys-Cu nanoparticles. Experimental results showed that the l-Cys-Cu-ICG and d-Cys-Cu-ICG nanoparticles displayed almost identical photothermal performance and singlet oxygen (O) generation capability in aqueous solution. However, upon laser irradiation, the d-Cys-Cu-ICG nanoparticles achieved enhanced anti-tumor effects compared to l-Cys-Cu-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.
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