What We Work On:

Combining Chemistry and Biology

Using our skills as chemists, we seek to develop new systems for diagnostics and drug delivery using the programmability and biocompatibility of DNA. We are currently working on projects to understand how DNA nanostructures behave in vivo.

Designing DNA-Minimal Architectures

Utilizing only a minimal set of DNA strands, we build unique 3D structures for uses in applications such as drug delivery and organization of other materials. This strategy allows us to make complex constructs using less DNA than other methods.

Expanding the DNA Toolbox

In the Sleiman lab, we work towards interfacing DNA with many other materials, including organic molecules, metals ions, and inorganic nanomaterials. We want to explore how DNA can be used to modify and organize these moieties.

Three Dimensional Cages and Nanotubes from DNA

A major research focus in our laboratory is the construction of DNA-based architectures for applications in biology and materials science.  Previous methods used only DNA to provide all design features, resulting in DNA-dense structures that are large and rigid.  We developed a new approach to DNA construction, in which synthetic molecules control and modify DNA self-assembly. We applied this strategy to three-dimensional DNA cages and nanotubes.  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.

We then reported a modular approach for the synthesis of DNA nanotubes, with ready control of geometry, size and stiffness of these assemblies, and ability to generate these in single-stranded ‘open’, and double-stranded ‘closed’ forms (Nature Nanotech. 2009, 349). We showed the encapsulation and selective release of cargo within our DNA cages (Nature Chem. 2010, 319Nature Chem 2013, 868) and the control of nanotube length (J. Am. Chem. Soc. 2010, 10212Nature Chem. 2015).  These cages can be reversibly anchored on lipid bilayers (JACS 2014, 12987).

We showed the efficient cellular uptake of 3D-DNA structures without transfection agents, nuclease resistance and gene silencing functionality into a number of cell lines. (JACS 2012, 2888Biomacromol. 2014, 276Chem. Sci. 2014, 2449, Nanoscale, 2015, ). We designed the first example of a DNA cube that can recognize a cancer-specific gene product, unzip and open into a two-dimensional structure as a result. This molecule is thus capable of revealing or releasing cargo conditionally, only if a cellular cancer marker is present. (Chem. Sci. 2014, 2449)

Interfacing DNA With Other Materials

DNA base-pairing is the central interaction in DNA assembly. However, this simple four-letter (A-T and G-C) language makes it difficult to create complex structures without using a large number of DNA strands of different sequences. Inspired by protein folding, we introduce hydrophobic interactions to expand the assembly language of DNA nanotechnology. Anisotropic decoration of hydrophobic polymers on one face of the cage leads to hydrophobically-driven formation of quantized aggregates of DNA cages, where polymer length determines the cage aggregation number. Hydrophobic chains decorated on both faces of the cage can undergo an intra-scaffold ‘handshake’ to generate DNA-micelle cages, which have increased structural stability and assembly cooperativity, and can encapsulate small molecules.

A particularly attractive strategy is to employ DNA nanostructures not as permanent scaffolds, but as transient, reusable templates to transfer essential information to other materials. To our knowledge, this approach, akin to top-down lithography, has not been examined. Our group has reported a molecular printing strategy that chemically transfers a discrete pattern of DNA strands from a three-dimensional DNA structure to a gold nanoparticle.  This provides control over the number of DNA strands and their relative placement, directionality and sequence asymmetry. Importantly, the nanoparticles produced exhibit the site-specific addressability of DNA nanostructures, and are promising components for energy, information and biomedical applications.

A major thrust of our research program is using existing solid-phase DNA synthesis methods to create sequence-controlled polymers and to interface these polymers with oligonucleotides. These methods can be used to then create perfectly monodisperse polymers with exact sequence control. We have used these strategies to create DNA-polymer micelles, as shown on the cover of Angewandte in 2014.

Understanding the Dynamics of DNA Nanostructures

In collaboration with the Cosa group at McGill University, we have also started working on developing single molecule imaging methodologies to better understand the dynamics of DNA nanostructures, in particular, nanotubes. This collaboration has also resulted in a publication on the cover of Nature Chemistry about the solid-phase synthesis of perfectly monodisperse DNA nanotubes.