Wilhelm Lecture — Designer Polypeptides and Electrostatic Assembly for RNA-Protein Enhanced Delivery

Wed, Oct 23, 2019, 4:00 pm to 5:00 pm

The traditional approach to mRNA delivery is the encapsulation of mRNA within a polycation; this approach requires mRNA to escape the polycation following endosomal uptake of the cargo, and to ultimately access the cytosol, where it can be translated.   The translation step requires binding of the mRNA capping protein, EIF4E, Eukaryotic translation initiation factor 4E; without this binding step, the mRNA is marked for degradation within the cell.  We recently demonstrated that the pre-encapsulation of the EIF4E cap pre-complexed with mRNA can enhance mRNA translation within cells by multifold in comparison to release of mRNA alone.  Furthermore, we found that a unique series of polypeptides with variable charged side chain structures can enhance encapsulation of mRNA with EIF4E, with optimal systems yielding 70 to 80 times that of the mRNA alone. A key to these polymers is their ability to cooperatively bind RNA with the associated protein machinery needed for translation together to enhance translation. More recently, we have found similar kinds of enhancements for the delivery of siRNA via co-complexation with the Ago-2 protein to create a pre-assembled version of RISC complex.   Finally, the layer-by-layer approach can be used to generate finely tuned release surfaces that can release small molecule, proteins, nucleic acids and other biologic drugs over sustained time periods, and with significant control of release characteristics.  This approach is particularly attractive for the delivery of proteins and nucleic acids such as siRNA.   By demonstrating efficacy in animal models, the promise of these material systems and their potential in biomedical applications will be highlighted.