Endocytosis Controls siRNA Efficiency: Implications for siRNA Delivery Vehicle Design and Cell-Specific Targeting

Vocelle, Daniel; Chan, Christina; Walton, S. Patrick

doi:10.1089/nat.2019.0804

Introduction: The plasma membrane protects a cell from the extracellular environment. As such it presents an obstacle that therapeutics needs to traverse in order to achieve efficacy. For example, small interfering RNAs (siRNAs) need to be delivered to the cytoplasm, where they can interact with the RNA interference machinery and initiate gene silencing. However, these macromolecules have poor membrane permeability, largely limiting their therapeutic potential. To address this challenge, current strategies involve encapsulating siRNAs into nanoparticles. However, upon cellular uptake, these nanoparticles are trapped in endosomes, which lack access to the cytoplasm. Towards developing an alternative strategy that provides direct access to the cytoplasm, we have been inspired by the unique capabilities of gap junctions to establish passageways between the cytoplasm of neighboring cells. Specifically, six connexins hexamerize to form a connexon hemichannel. Two hemichannels from neighboring cells dock to each other to form a complete gap junction channel, facilitating the exchange of molecular cargoes such as ions and siRNA. Therefore, incorporating the gap junction network into therapeutic delivery materials has the potential to enhance the delivery efficiency of siRNAs by directly depositing siRNAs into the cytoplasm.

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