Nucleic acids (RNA and DNA) are a new class of highly selective therapeutics: they can treat diseases that are challenging or impossible to treat with small-molecule pharmaceuticals.
However, there are still considerable obstacles preventing nucleic acid therapies from being widely used in medical settings: nucleic acids are difficult to deliver to organs beyond the liver and kidneys, and they show poor cellular penetration.
Our research program aims to develop DNA nanostructures that overcome the challenges associated with the delivery of nucleic acid therapies, precisely delivering these therapies to cancer cells, and advancing the field of precision cancer treatment (oncology). Our nanostructures target cancer-driving molecules that are patient-specific and stimulate the immune system to recognize and kill tumors.
In order for these materials to reach their full potential, however, we must also develop an understanding of their cellular uptake. We recently reported that intracellular fluorescence, and even FRET signals, cannot necessarily be correlated with the cellular uptake of intact DNA structures, highlighting the need for new methods to quantify the biological properties of DNA nanostructures, an area that we are actively working in. (ACS Cent. Sci. 2019) .
A major research focus in our laboratory is the construction of 3D DNA-minimal “wireframe” architectures that require far fewer unique DNA sequences than other methodologies. Using this approach, we showed the first modular synthesis of prismatic DNA cages with deliberate variation of size and geometry, and controlled size switching with added DNA strands (JACS 2007, ChemComm. 2011, JACS, 2012). We also reported DNA cages (Nat. Chem. 2013) and DNA nanotubes (Nat. Chem. 2015, ACS Nano 2013), where geometry, length (Nat. Commun. 2015) and dynamic character (ACS Nano 2015, ACS Nano 2018) could be precisely varied and controlled.
Additionally, we developed a new approach to DNA construction, in which synthetic molecules control and modify DNA self-assembly (Science 2008, Chem. Soc. Rev. 2011, Nat. Rev. Mater. 2017).
Our group works towards expanding on the biological DNA “alphabet” of adenine, thymine, guanine, and cytosine. By interfacing DNA strands with inexpensive small molecules such as cyanuric acid, we have found that their assembly can be reprogrammed, generating fibrous structures (Nat. Chem. 2016).
DNA structures can also be used as impermanent scaffolds to create programmable materials. Functioning as a molecular “printing press”, information contained in DNA architectures can be transferred onto gold nanoparticles that then become just as programmable as the original structure. (Nat. Chem. 2016) We recently applied the concept of DNA printing to synthetic polymers (Nat. Chem. 2018) and even small molecule (Angew. 2019) further expanding the library of materials that can be encoded with DNA’s structural addressability.
Using solid-phase chemistry based on the phosphoramidite synthesis of DNA, we also develop new methods for the generation of sequence-defined polymers (J. Org. Chem 2018). By interfacing DNA with hydrophobic polymers, for example, new self-assembly properties can be accessed (JACS 2018, JACS 2016).