470426 Unlocking Intracellular Therapeutic Targets through Novel Nanostructured Biomaterials
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.