"Macromolecular drugs such as DNA and proteins often require cell or organelle-specific delivery to be effective. For example, DNA for gene delivery is transcribed within the nuclei of target cells. Therapies employing the p53 tumor suppressor are also active within the nucleus, while compounds to treat certain neurodegenerative diseases are directed towards altering mitochondrial function.
We are focused on engineering biomolecular strategies for improving the efficiency of payload delivery to pre-determined cellular/sub-cellular locations. A significant proportion of our work is focused on the development of synthetic materials capable of protecting and transporting DNA and RNA in vivo. Specifically, we are interested in understanding how the chemical and physical interactions between our materials and the biological environment affect their stability and structure. Changes in material structure can render delivered therapies ineffective or cause undesirable side effects. Conversely, we are also developing methods to pre-program desirable material responses that improve drug targeting or transport. We are currently exploring the following design strategies:
1.Self-evolving nanomaterials:
Biological membranes and vesicles play a critical role in functional compartmentalization and biotransport, making vesicles one of the ultimate biomimetic systems for drug and gene delivery. Great progress has been made in the development of liposomal delivery systems; however, liposome-based systems suffer from stability issues, making it difficult to effectively functionalize and tailor them for targeted transport in a diverse biological environment. We are designing novel, bio-responsive, polymeric nano-vesicle and nanoparticulate systems for the efficient transport of therapeutic compounds. These materials rely on the natural self-assembly of synthetic and natural macromolecules in aqueous media, and contain functional peptide linkages capable of self-directing their own transport through the extracellular and intracellular environment.
2.Scaffold-mediated delivery:
Strategies to improve tissue/ECM regeneration would have broad impacts on healthcare, and depend both on our identification of the factors that control ECM deposition and remodeling, and on the development of mechanisms to appropriately alter cellular expression of these factors. With this in mind, we are developing strategies for spatio-temporally controlled nucleic acid delivery to cells within tissue engineering scaffolds, based on a unique mechanism for nucleic acid incorporation. This system will allow cell-initiated and cell-specific nucleic acid delivery, and is targeted towards the systematic investigation of the influence of growth factor (and other protein) overexpression or suppression on ECM assembly.
3.Reversible DNA scaffolds:
Non-viral DNA delivery is currently extremely inefficient, and requires millions of DNA molecules per cell to obtain reasonable transfection levels. A critical and unsolved issue is how to trigger the release of DNA specifically within the nucleus of a cell: current DNA packaging techniques involve complexing DNA with polycationic lipids or polymers to protect it from degradation, but these same packaging techniques prohibit DNA transcription. To address this issue, we are designing novel, self-unpackaging gene delivery scaffolds based on the self-assembly of DNA with peptide-based nanomaterials. These scaffolds will be capable of reversibly regulating DNA accessibility: during extracellular and intracellular transport, packaged DNA (?nanoplexes?) will be inaccessible to DNases and protected from shear-induced degradation; once delivered to the nucleus, the scaffolds will interact with natural nuclear proteins to promote nanoplex loosening and transcriptional activity."
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