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Branched Amphiphilic Peptide Capsules (BAPCs) as a Delivery Systems for mRNA vaccines

 

Messenger RNA (mRNA) vaccines are emerging as a potential and powerful alternative nucleic acid-based vaccines. The lack of their genome integration and the high potential to evoke cytolytic T cell responses, have placed them as a safe and potent alternative to DNA vaccines. Nowadays, direct in vivo administration of mRNA has shown promising results. However, when applied directly in vivo, mRNA vaccines strongly benefit from wrapping the mRNA into nano-sized carriers. This association can reduce mRNA degradation and promote cellular uptake.  Our research group is currently working with a new class of nano-sized carrier made of branched amphiphilic peptide capsules (BAPCs). These nanocapsules have unusual but highly desirable properties that could address some of the shortcomings associated with other nanoparticles. For instance, they are water soluble, stable in blood and made entirely of natural compounds. Additionally, these short vesicle-forming peptides (15-23 residues) can be synthesized economically and assembled easily by users. They are formed through the self-assemble of two branched peptide sequences bis(Ac-FLIVI)-K-KKKK-CO-NH2 and bis(Ac-FLIVIGSII)-KKKKK-CO-NH2 derived from a human transmembrane channel sequence(Fig. 1).

Figure 1. Branched Amphipathic Peptide Capsule (BAPC) Forming Sequences. The above peptides are described in the text as (Ac-FLIVI)2-K-K4-CO-NH2 & (Ac-FLIVIGSII)2-K-K4,-CO-NH2 respectively.

In the presence of DNA, they can act as cationic nucleation centers around which DNA wraps (Fig. 2A-C). We demonstrated that BAPCs were capable of delivering a vaccine DNA encoding E7 oncoproteins of HPV-16 (pgDE7) in mice. Mice immunized with pgDE7-BAPC nanoparticles managed to constrain tumor growth up to one month after transplantation of tumor cells without significant toxic effects.  Furthermore, survival time was enhanced by two-fold in comparison to the control group.  We are currently testing the ability of BAPCs to delivery mRNA vaccines in murine models using the antigen model OVA.

Figure 2: TEM images of the BACP:DNA nanoparticles at N:P = 20.8. (A) Single BAPCs interacting with pDNA. Scale bar = 10 nm. (B) Cluster of BAPCs interacting with DNA. Scale bar = 100 nm. (C) Schematic representation of potential BAPC-DNA interactions.