Regulating gene expression through the intracellular delivery of small interfering RNA (siRNA) holds great promise as a strategy to study and treat cancer. Unfortunately, naked nucleic acids display limited cell uptake because of their high molecular weight and negative charge, and those that are internalized are at risk of degradation in endosomal and lysosomal compartments or by cytosolic enzymes. Researchers have developed various nanocarriers to shuttle siRNAs into cells and protect them from premature degradation, but clinical translation of these carriers has been slow because there is limited knowledge regarding the parameters that dictate their biological interactions. We have developed two different types of siRNA nanocarriers and performed detailed studies to elucidate the mechanisms by which they operate inside cells. First I will discuss our work with polyethylenimine-coated spherical nucleic acids (PEI-SNAs), in which PEI is wrapped around a spherical nucleic acid core containing radially oriented siRNA. We have demonstrated that these PEI-SNAs undergo enhanced and more rapid cellular uptake than randomly assembled PEI-siRNA polyplexes, exhibit decreased lysosomal accumulation, enable more potent gene knockdown, and are more cytocompatible. These findings demonstrate that nanocarrier architecture plays a critical role in gene silencing efficiency. Second, I will discuss our work developing nanoshell-siRNA conjugates for temporal control over gene regulation. These nanocarriers keep their nucleic acid cargo inactive until it is released on-demand by externally applied pulsed near-infrared light, which is desirable because it prevents unintended widespread gene regulation. We have extensively characterized the mechanisms of siRNA release from nanoshells upon pulsed irradiation, and we have also shown that light-triggered gene silencing mediated by siRNA-nanoshell conjugates is considerably more potent than using commercial transfection agents to deliver siRNA into cells. Overall, our findings indicate the importance of thoroughly characterizing the biological interactions of RNA nanocarriers for applications in therapeutic gene regulation.

Improving intracellular RNA delivery through nanocarrier design

256th National Meeting (2018)

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