Notable Achievements:1) Development of a novel DNA data storage technology, where an original "molecular movable type printing" parallel writing strategy was proposed. This achievement enabled the storage of 275,000 bits of unconventional DNA data, marking a 300-fold increase in scale compared to the highest international standards (Nature, 2024). It has laid a critical technological foundation for the practical application of DNA storage.2) Construction of a new type of DNA computing circuit based on innovative allosteric regulation principles at the molecular level. Developed allosteric signal networks and computational systems achieved non-contact directional transmission of allosteric signals at a 100nm scale (Science Advances, 2022), as well as precise regulation of tumor cells through programming DNA/protein allosteric networks (Nature Communications, 2023). These advancements have opened up new avenues for molecular logic computing and intelligent diagnosis and treatment.3) Proposal of a "subtractive manufacturing" inspired strategy for manipulating DNA nanomaterials within molecular machines, allowing for fine control over the distribution of DNA chains on individual 15nm gold particles (Angew. Chem. Int. Ed., 2023). This work is anticipated to enable precise manipulation of molecular data structures.4) Establishment of a simple yet versatile method for creating more efficient entropy-driven DNA circuits aimed at molecular programming and synthetic biology (JACS, 2019), contributing to the advancement of these fields by providing enhanced tools and methodologies.

Parallel DNA storage

(Cheng Zhang*, et. al., Parallel molecular data storage by printing epigenetic bits on DNA. Nature, 34, 824-832, 2024)

We presented an alternative, parallel strategy that enables the writing of arbitrary data on DNA using premade nucleic acids. Through self-assembly guided enzymatic methylation, epigenetic modifications, as information bits, can be introduced precisely onto universal DNA templates to enact molecular movable-type printing. By programming with a finite set of 700 DNA movable types and five templates, we achieved the synthesis-free writing of approximately 275,000 bits on an automated platform with 350 bits written per reaction. The data encoded in complex epigenetic patterns were retrieved high-throughput by nanopore sequencing.

Fig.1. Parallel DNA storage to write 275,000 bits epigenetic information

Protein-oligonucleotide allosteric logic circuits

(Liang Yuan, et. al., Cheng Zhang*, Programming conformational cooperativity to regulate allosteric protein-oligonucleotide signal transduction, Nature Communications, 14, 4898, 2023)

We are now interested in developing complex molecular circuits and computing operations to facilitate signal transmission and the applications in vitro and in cellular environment. Currently, we are working on: recyclable complex DNA circuit, DNAzyme regulated molecular circuits, cascading transcription circuits. Currently we are working on integrating the in vitro DNA circuit into cells, thus achieving in vivo molecular diagnosis and information signaling in cell. In addition, regulable DNA circuit can also be used to construct dynamic nanodevices, which is another interest in our research.

Fig.2. An allosteric protein-oligonucleotide signal transduction system

Programmable allosteric DNA regulations for networks and nanomachines

(Cheng Zhang*, et. al., Programmable Allosteric DNA Regulations for Molecular Networks and Nanomachines, Science Advances, 8, eabl4589, 2022)

Because of the unique structural and optical properties, organizing AuNPs with DNA assembly structures in a well- controlled manner has attracted a lot of attention in the fields of biosensing and nanodevices. The DNA nanostructures offer addressable substrate for nanoparticle spatial attachment. Our goal is coupling various assembled nanostructures and specific spatial nanoparticle modifications, thus constructing versatile tunable nanoparticle assembly nanostructures.

Fig.3. An allosteric DNA regulations and molecular nanomachines

Spatially Programmable DNA Nanorobot Arm to Modulate Anisotropic Gold Nanoparticle Assembly

(Jing Yang, et. al., Cheng Zhang*, Spatially Programmable Enzymatic Nanorobot Arm to Modulate Anisotropic Gold Nanoparticle Assembly, Angewandte Chemie International Edition, 62, e202308797, 2023)

We developed a strategy of using a spatially programmable enzymatic nanorobot arm to modulate anisotropic DNA surface modifications and assembly of AuNPs. Through spatial controls of the proximity of the reactants, the locations of the modifications were precisely regulated. We demonstrated the control of the modifications on a single 15 nm AuNP, as well as on a rectangular DNA origami platform, to direct unique anisotropic AuNP assemblies.

Fig.4. Spatially Programmable Enzymatic excision to control anisotropic DNA/AuNPs assemblies

Recyclable DNA circuits

(Cheng Zhang*, et. al., Nicking Assisted Reactant Recycle to Implement Entropy-Driven DNA Circuit, J. Am. Chem. Soc., 141, 17189-17197, 2019)

We described the implementation of a nicking-assisted recycling strategy for reactants in entropy-driven DNA circuits, in which duplex DNA waste products are able to revert into active components that could participate in the next reaction cycle. Both a single layered circuit and multiple two-layered circuits of different designs were constructed and analyzed. During the reaction, the single-layered catalytic circuit can consume excess fuel DNA strands without depleting the gate components.

Fig.5. Nicking-assisted recyclable entropy-driven DNA circuits