Nanozymes with bioorthogonal reaction for intelligence nanorobots

Abstract

Bioorthogonal reactions have attained great interest and achievements in various fields since its first appearance in 2003. Compared to traditional chemical reactions, bioorthogonal chemical reactions mediated by transition metals catalysts can occur under physiological conditions in the living system without interfering with or damaging other biochemical events happening simultaneously. The idea of using nanomachines to perform precise and specific tasks in living systems is regarded as the frontier in nanomedicine. Bioorthogonal chemical reactions and nanozymes have provided new potential and strategies for nanomachines used in biomedical fields such as drug release, imaging, and bioengineering. Nanomachines, also called as intelligence nanorobots, based on nanozymes with bioorthogonal reactions show better biocompatibility and water solubility in living systems and perform controlled and adjustable stimuli-triggered response regarding to different physiological environments. In this review, we review the definition and development of bioorthogonal chemical reactions and describe the basic principle of bioorthogonal nanozymes fabrication. We also review several controlled and adjustable stimuli-triggered intelligence nanorobots and their potential in therapeutic and engineered applications. Furthermore, we summarize the challenges in the use of intelligence nanorobots based on nanozymes with bioorthogonal chemical reactions and propose promising vision in smart nanodevices along this appealing avenue of research.

Keywords: Bioorthogonal reaction; Nanorobotics; Nanozymes.

Figure 1

Chemical signals and pH-controlled nanorobotics. A Intracellular catalytic processes. Catalytic activity inhibited by steric hindrance of gatekeeper CB[7] and recovery of catalytic activity after adding ADA which can combine with CB[7], translating non-toxic prodrug into toxic drug. B Non-toxic prodrug activated by Pd catalyst to toxic drug. Reproduced with permission of Nature Publishing Group (Tonga et al. 2015). C Selective targeting of infected biofilms of Au nanorobotics mediated by change of the surface charge in different pH and translation of pro-fluorophores to fluorescent products identify their catalytic activity. Reproduced with permission of American Chemical Society (Gupta et al. 2018).) D Structure of CB[7], ADA catalyst (Ru and Pd), and the universal constituent parts of Au nanoreactor. Reproduced with permission of Nature Publishing Group (Tonga et al. 2015), and American Chemical Society (Gupta et al. 2018)

Figure 2

Temperature and light signals controlled nanorobotics. A The mechanism of substrate catalyzed by structurally variable nanorobotics under different temperature. B Catalyst presents activity toward prodrug in 37 °C. Reproduced with permission of Elsevier Inc. (Cao-Milán et al. 2020). C Conversion between trans-azobenzene and cis-azobenzene under UV light and visible light induces disaggregation and recombination of cyclodextrin which is used for conceal catalyst. D Prodrug activated by nanorobotic to toxic form under UV light. E Structure of trans-azobenzene, cis-azobenzene, palladium (Pd) and cyclodextrin (CD). Reproduced with permission of Nature Publishing Group (Wang et al. 2018). F Biofilm viability of different treatment groups under 37 °C and 25 °C. Reproduced with permission of Elsevier Inc. (Cao-Milán et al. 2020). G Cell viability with different treatment showing controlled catalytic activity. Reproduced with permission of American Chemical Society (Wang et al. 2019)

Figure 3

Bioorthogonal reaction used for prodrug activation. A Schematic diagram of prodrug activation. Reproduced with permission of Nature Publishing Group (Li and Chen 2016). B Reaction mediated by palladium catalyst and structures of pro-Cou-NCl, NCl and catalyst. C Intracellular toxicity introduced by the activated prodrug. Reproduced with permission of Elsevier Ltd. (Li et al. 2017). D Conversion of inactive prodrug to cytotoxic HDAC inhibitor under catalysis of Pd-Exo^A549. E Selective action showed by incubating Pd-Exo^A549 with cell A549 and U87. Reproduced with permission of Nature Publishing Group (Sancho-Albero et al. 2019). F Prodrug transformed to toxic umbelliprenin by ruthenium-bound GArM complexes. G Cellulo activity of A549 cells after different disposition. Reproduced with permission of Nature Publishing Group (Eda et al. 2019)

Figure 4

Bioorthogonal reaction used for genetic engineering. A Specific process of gene regulation catalyzed by Ruthenium complexes modified by biotin-streptavidin technology. B Structure of cell-penetrating biotin-streptavidin system and its two main components-Ruthenium complex and fluorescent TAMRA moiety. C Structure of compounds and relevant reactions used for constructing gene switch. Reproduced with permission of Nature Publishing Group (Okamoto et al. 2018)

Figure 5

Bioorthogonal reaction used for protein engineering and cell engineering. A Basic principle of reaction mediated by bioorthogonal enzyme. B P450_BM3 variants with various enzymatic activity designed with protein engineering catalyze substrates and produce different intensities of fluorescence. Reproduced with permission of John Wiley and Sons Ltd. (Ritter et al. 2015). C A chemical decaging strategy based on palladium-mediated reactions for generating Neu on live cells. Neu5Proc can be converted into the core neuramic acid and can be metabolically incorporated into cell-surface sialylated glycans. D Surface-charge variation and confocal microscopy imaging before and after treatment with Pd NPs. Pd-mediated depropargylation of surface-displayed Neu5Proc caused significant cell clustering that was not observed without Pd NPs or Neu5Proc. Scale bars: 10 μm. Reproduced with permission of John Wiley and Sons Ltd. (Wang et al. 2015)