470426 Unlocking Intracellular Therapeutic Targets through Novel Nanostructured Biomaterials

Tuesday, November 15, 2016: 3:15 PM
Golden Gate 6 (Hilton San Francisco Union Square)
Millicent O. Sullivan, Chemical and Biomolecular Engineering, University of Delaware, Newark, DE

Nucleic acid cargoes offer unmatched diversity in gene regulatory potential and therapeutics, and understanding of nucleic acid functionality continues to expand rapidly and dramatically through seminal discoveries including RNA interference approaches and gene editing technologies. In nature, the basis for gene regulation is ultimately encoded by the exquisite specificity with which cells are able to control both the location and accessibility of nucleic acid constructs to govern their activation states. My research program seeks to mimic these activities through the design of stimuli-responsive synthetic materials whose interactions with nucleic acids and cells can be controlled dynamically by specific intracellular or external triggers. We exploit our ability to regulate binding/release and cellular processing to gain new mechanistic insights over nucleic acid delivery mechanisms.

This presentation will outline recent work in my laboratory to develop peptide and polymer constructs that respond to specific intracellular signals (e.g. enzymes) or exogenous stimuli (e.g. light) to control the release of plasmid DNAs and siRNAs, respectively, and thereby enhance nucleic acid activity while enabling spatiotemporal control over gene suppression/activation. Specifically, in one case, we capitalized on newly recognized and highly pivotal roles for histone tails in native gene regulatory control to develop a gene transfer method that utilizes native, histone-based processing pathways via incorporation of post-translationally modified (PTM) histone tails within controllably-assembled DNA vehicles (polyplexes). Our efforts proved that polyplexes displaying PTM-modified histone tails promote nuclear accumulation, DNA release, transcription, and enhanced transfection. Moreover, our group has combined detailed nanostructure engineering with sophisticated cellular imaging to identify novel aspects in the cell biology framework regulating polyplex transport to the nucleus. In another example, we have developed versatile and highly tunable light-based strategies to release siRNAs with control at cellular length scales. Light-triggered delivery materials exhibit innate advantages in spatiotemporal control as compared with chemically responsive delivery materials or strategies to control nucleic acid exposure based upon “stamping” or liquid-liquid patterning, yet existing light-triggered nucleic acid delivery materials have minimal dynamic range in gene modulation. We demonstrated a new class of light-sensitive polymers that provide biocompatibility and rapid application with proven on/off initiation of gene silencing and the ability to locally “dial-in” the level of siRNA deployment and gene regulation. The ability to control the spatial placement and induction of biomolecular signaling programs through this on/off switch will be essential in developing and modeling complex tissues such as cardiovascular and neural networks.

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See more of this Session: Area Plenary: Bionanotechnology II
See more of this Group/Topical: Nanoscale Science and Engineering Forum