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The Bathe BioNanoLab engineers revolutionary new materials at the nanometer-scale, or nanoscale, using nucleic acids. Major goals of these materials is to enable the targeted delivery of therapeutic nucleic acids (siRNA, messenger RNA, and CRISPR) to any organ in the body including the brain to treat over 7,000 genetic diseases and cancer; mimic virus structures to make vaccines that generate immunity against deadly infectious diseases including HIV; harvest and transport energy from the sun to make highly efficient, biomimetic solar cells; and fabricate quantum computers that operate at room temperature to overcome the end of Moore’s Law. These revolutionary applications of nucleic acid nanotechnology are discussed below in more detail.

Structural DNA & RNA Nanotechnology

DNA is commonly known as a carrier of genetic information. As a sequence-programmable polymer, DNA can also be used to program complex 2D and 3D materials at the nanometer-scale. DNA’s sequence programmability together with its ability to be functionalized chemically enables nearly any nanomaterial to be fabricated using DNA including virus-like particles for vaccine or therapeutic delivery; light-harvesting materials that host dye molecules for nanoscale energy transport; as well as quantum dots for quantum sensing and computing. The overall size of the icosahedral DNA nanoparticle shown at left is approximately 40 nanometers, whereas the diameter of the duplex of DNA shown composing each edge of the nanoparticle is 2 nanometers, and the thickness of a human hair is approximately 10,000 to 100,000 nanometers.

Viral-like Nanoparticles for Vaccines & Therapeutic Delivery

Natural viruses contain proteins on their outer coat that enables them to evade the immune system, enter into cells, and integrate their genomic DNA into their host’s genome. Structured DNA nanoparticles can be used to mimic certain aspects of viruses in order to either target tissues and cells for delivery of therapeutic payloads, or activate immune cells for vaccination. In this research area we are using structured DNA and RNA nanoparticles to enable the targeted delivery of therapeutic siRNA, mRNA, and CRISPR to organs and tissues including the central nervous system to deliver treatments and cures for diseases of the brain. In parallel research, we are also using these virus-like particles to stimulate the humoral immune system to make effective vaccines to protect against infectious diseases such as HIV. The virus-like DNA nanoparticle shown is bearing 10 copies of an antigenic protein used for a vaccine application (scale bar is 10nm).

Quantum Sensing and Computing

Natural photosynthetic complexes consist of densely packed arrays of chlorophyll molecules that facilitate photon adsorption and energy transfer for the production of the chemical fuel ATP, which is the origin of energy for life on planet earth. Programmed self-assembly of synthetic DNA into precise 2D and 3D nanoscale architectures that mimic natural light-harvesting systems can now be used to organize chromophores to replicate key aspects of bacterial photosynthetic systems, controlling how energy and quantum information are transported at the nanoscale. In this research, we are fabricating structured DNA assemblies with embedded chromophores to understand how to efficiently harness energy from the sun, as well as engineer new qubits—the computing unit of quantum computers—that operate at room temperature. (Figure is courtesy Ella Maru Studio.)

Molecular Computing, Data Storage & Retrieval

The 4-letter ATGC code of DNA in our cells encodes approximately 1 gigabyte of information  per human genome, packaged up neatly within the nucleus of the cell. Synthetic DNA can similarly be used as a storage medium to contain files and other data in an extremely compact manner such that the entire world’s information could in principle fit in the palm of our hand if encoded in DNA. However, retrieving information or files from such “pools” of data encoded in DNA is a highly non-trivial task, since this information is in principle unstructured and disorganized. An analogy would be finding a page or chapter from a book in the US Library of Congress if all of its books were simply piled into the center of a football stadium. In this research area our lab is using DNA nanoparticles to organize and structure data and information stored in DNA, and developing ways to both randomly access arbitrary pools of data ranging from 1 MB to 1 GB from a pool of 1 Exabyte of data (1 Exabyte is 1 billion GB), as well as to compute using these molecular datasets, ranging from machine learning to data sorting and image recognition. Figure from Scientific American.

profiling neurons to understand Mutations associated with Autism

Genetic studies have now revealed dozens of mutations associated with autism spectrum disorder (ASD) that affects approximately 1 in 36 children in the US alone. The majority of these mutations are associated with neuronal synapse proteins, which regulate signal transmission in the brain. In order to develop successful therapeutics to treat ASD, it is therefore essential to understand how these mutations impact neuronal synapse structure and function, and ideally in patient-derived neuronal samples from induced pluripotent stem cells. Toward this end we are developing highly multiplexed fluorescence imaging of neuronal synapse proteins, mRNAs, and neuronal activity to offer deep, multimodal profiling of neuronal synapse structure and function with barcoded nucleic acid imaging probes. This neuronal profiling platform will enable downstream discovery of new therapeutics to treat ASD, as well as other neurodevelopmental diseases and disorders such as schizophrenia.

programming custom rna catalysts

RNAs perform a variety of important roles in cells, from acting as trans regulators (e.g. siRNA and lncRNA) of many cellular processes to catalyzing peptide bond formation in the ribosome. The tertiary structure of RNA plays a critical role in its binding and catalytic function, which is extremely challenging to predict or engineer. In this research area we are using programmed nucleic acid assemblies to coordinate synthetic RNA sequences to endow them with catalytic properties de novo, or that replicate and improve on existing enzymes such as the ribosome. This research will ultimately enable cell-free production of materials and chemicals using custom RNA-based enzymes.

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