DNA nanotechnology takes DNA molecule out of its biological context to build nanostructures that have entered the realm of robots and thus added a dimension to cyborg and bionic systems. Spurred by spring-like properties of DNA molecule, the assembled nanorobots can be tuned to enable restricted, mechanical motion by deliberate design. DNA nanorobots can be programmed with a combination of several unique features, such as tissue penetration, site-targeting, stimuli responsiveness, and cargo-loading, which makes them ideal candidates as biomedical robots for precision medicine. Even though DNA nanorobots are capable of detecting target molecule and determining cell fate via a variety of DNA-based interactions both in vitro and in vivo, major obstacles remain on the path to real-world applications of DNA nanorobots. Control over nanorobot’s stability, cargo loading and release, analyte binding, and dynamic switching both independently and simultaneously represents the most eminent challenge that biomedical DNA nanorobots currently face. Meanwhile, scaling up DNA nanorobots with low-cost under CMC and GMP standards represents other pertinent challenges regarding the clinical translation. Nevertheless, DNA nanorobots will undoubtedly be a powerful toolbox to improve human health once those remained challenges are addressed by using a scalable and cost-efficient method.

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Self-Assembly of DNA Molecules: Towards DNA Nanorobots for Biomedical Applications

Artificial molecular machines have found widespread applications ranging from fundamental studies to biomedicine. More recent advances in exploiting unique physical and chemical properties of DNA have led to the development of DNA-based artificial molecular machines. The unprecedented programmability of DNA provides a powerful means to design complex and sophisticated DNA-based molecular machines that can exert mechanical force or motion to realize complex tasks in a controllable, modular fashion. This Perspective highlights the potential and strategies to construct artificial molecular machines using double-stranded DNA, functional nucleic acids, and DNA frameworks, which enable improved control over reaction pathways and motion behaviors. We also outline the challenges and opportunities of using DNA-based molecular machines for biophysics, biosensing, and biocomputing.

https://pubs.acs.org/doi/pdf/10.1021/jacsau.2c00292

DNA-Based Molecular Machines

Natural ligand–receptor interactions that play pivotal roles in biological events are ideal models for design and assembly of artificial recognition molecules. Herein, aiming at the structural characteristics of the spike trimer and infection mechanism of SARS-CoV-2, we have designed a DNA framework-guided spatial-patterned neutralizing aptamer trimer for SARS-CoV-2 neutralization. The ∼5.8 nm tetrahedral DNA framework affords precise spatial organization and matched valence as four neutralizing aptamers (MATCH-4), which matches with nanometer precision the topmost surface of SARS-CoV-2 spike trimer, enhancing the interaction between MATCH-4 and spike trimer. Moreover, the DNA framework provides a dimensionally complementary nanoscale barrier to prevent the spike trimer–ACE2 interaction and the conformational transition, thereby inhibiting SARS-CoV-2–host cell fusion and infection. As a result, the spatial- and valence-matched MATCH-4 ensures improved binding affinity and neutralizing activity against SARS-CoV-2 and its varied mutant strains, particularly the current Omicron variant, that are evasive of the majority of existing neutralizing antibodies. In addition, because neutralizing aptamers specific to other targets can be evolved and assembled, the present design has the potential to inhibit other wide-range and emerging pathogens.

Spatial- and Valence-Matched Neutralizing DNA Nanostructure Blocks Wild-Type SARS-CoV-2 and Omicron Variant Infection

Spherical nucleic acids (SNAs) are three-dimensional and polyvalent nanostructures with highly oriented and densely arranged nucleic acids shell attached to the surface of nanomaterials cores. Owing to the versatile photophysical and chemical properties, unique programmability, specific recognition affinity, excellent biocompatibility and cellular uptake efficiency, SNAs have been utilized to engineer intelligent biosensors for in situ analysis and sensing intracellular cancer biomarkers. To afford a valuable and systematic guidance for cancer diagnosis with SNAs nanotechnology, we summarize recent advances and applications of SNAs-based biosensors for tracking and imaging cancer-related biomarkers, and discuss the future challenges and opportunities of SNAs for cancer diagnosis. 

Spherical nucleic acids-based biosensors for cancer biomarkers detection

Liquid environment is essential for the occurrence of various vital processes in fields of chemistry, biology, mechanics, and so on, underscoring the importance of understanding the solid–liquid interfaces. In the past decades, liquid‐environment atomic force microscopy (LE‐AFM) has played a nonsubstitutable role in studying solid–liquid interfaces because of its sub‐nanometer spatial resolution, video‐level imaging rates as well as piconewton‐level force measuring capabilities. Various state‐of‐the‐art developments and exciting applications are made recently. In this review, following a brief discussion on the development history of LE‐AFM, its working principles and operating modes with an emphasis on challenges posed by liquid environments and the corresponding solutions are introduced. As tip–sample interactions set the basis of all kinds of AFM, the interactions between the tip and the sample in liquid, including long‐range DLVO forces with quantitative description and short‐range non‐DLVO, whose physical origination is, by contrast, still in ambiguous, are elaborated. The applications of LE‐AFM are then summarized in four aspects, including high‐resolution imaging, high‐speed imaging, tribological characterization, and force spectroscopy‐based characterization. Finally, the perspectives on the future developing direction of LE‐AFM are shared.

Qingting Li

Papers

DNAs catalyzing DNA nanoconstruction