Chiral iron single-atom nanozymes for enhanced photothermal chemodynamic cancer therapy

Chirality is prevalent in nature and is one of the most prominent biochemical features of life, playing a crucial role in maintaining the normal functioning of living cell or organism. In recent years, chiral nanomaterials prepared by chiral exchange strategies have attracted widespread interest due to their specific chiral-dependent biological effects, which have promoted a wide range of potential applications in the fields of biology and medicine. It has been found that the chirality of the surface ligands significantly affects the ensuing biological applications of inorganic nanomaterials, providing a scientific foundation for the use of chiral inorganic nanomaterials in tumor therapeutic scenarios. However, current research on the antitumor properties of chiral nanomaterials is mainly focused on the nanoscale-level. The low metal utilization and poor metabolisability of metal-based nanomaterials have hindered their further development in biomedical applications. Therefore, it is important to construct tumor microenvironment (TME)-responsive, ultrasmall, safe chiral nanomaterials and understand the interactions between organisms and chiral nanomaterials for the facilitation of precision medicine.

Single-atom nanozymes (SAzymes) are regarded as potential nanozyme materials for promoting various catalytic reactions. SAzymes with isolated active metal centers anchored to solid supports have several advantages, including the complete metal utilization, high selectivity, and highly effective catalytic activity. The maximum atom utilization efficiency ensures the atom economy for metal use of the abundant well-defined active catalytic sites. Owing to these outstanding merits, SAzymes have attracted much attention in the field of catalytic tumor therapy. In particular, chemodynamic therapies represented by iron single-atom nanoenzymes are making a big splash in tumor therapy. However, drawbacks like low biocompatibility and instability of iron single-atom nanoenzymes restrict their application in tumor therapy. Hence, the precise and directed design of single-atom nanomaterials is of great significance for improving their bioavailability and the efficiency of tumor therapy. Covalent organic frameworks (COFs) contain no extraneous metals, allowing pyrolysis to eliminate interference from other metal elements. Their imine bonds readily coordinate with metal atoms while exhibiting excellent thermal stability, making them ideal supports for single-atom catalysts.

In this research, we designed chiral iron single-atom nanoenzymes by an adsorption-pyrolysis strategy. Chiral iron single-atom nanoenzymes (L/D-Cys@SAFe/NC) were synthesized by modifying SAFe/NC through mutual electrostatic interactions using L/D-Cys as a chiral inducer. On the one hand, the nanoenzymes exhibit excellent POD-like and GSH-OXD enzyme activities. On the other hand, the nanoenzymes can generate local high temperatures in cancerous tissues under 808-nm laser irradiation, endowing them with promising photothermal agents for photothermal therapy (PTT) [40-43]. Notably, the elevated temperature in the tumor region not only ablates the tumor more efficiently, but also accelerates the Fenton reaction to produce large quantities of ·OH, thereby leading to a synergistic effect of PTT, CDT and ferroptosis in tumor therapy. To explore the effect of chirality on cytotoxicity, we investigated the antitumor capabilities of L/D-Cys@SAFe/NC nanoenzymes in vitro and in vivo. The results showed that tumor cells were more capable of internalising D-Cys@SAFe/NC than L-Cys@SAFe/NC (2.17 times). The corresponding mouse experiments in vivo confirmed that D-Cys@SAFe/NC exhibited more effective tumor ablation effects. This study provides insights into the differences resulting from chiral-cellular interaction forces and chiral single-atom nanoenzymes for biological applications, highlighting the vast clinical potential.

Other contributors include Fuying Chen, Guodong Cheng, Lingyu Sun and Qihui Dang from the School of Linyi University, Qilu Normal University and the Key Laboratory of Advanced Biomaterials and Nanomedicine in Universities of Shandong; and Bowen Sun, Zunfu Hu, Zhichao Dai from the School of Linyi University and the Key Laboratory of Advanced Biomaterials and Nanomedicine in Universities of Shandong.

This work was supported by the National Natural Science Foundation of China (No. 22075122 and 22371108), Natural Science Foundation of Shandong Province (No. ZR2020QB170 and ZR2024MB125), Taishan Scholar Foundation of Shandong Province (tsqn202211242).

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