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. These and other RNA nanocomplexes will be examined, with an emphasis on polypeptide design using poly(propargyl glutamate) (PPLG) and aminated derivatives of poly(benzyl aspartate).<br/>

Designer polypeptides for enhanced RNA and helper protein co-delivery

2019 Spring National Meeting

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