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Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles.

McCullough KC, Milona P, Thomann-Harwood L, Démoulins T, Englezou P, Suter R, Ruggli N - Vaccines (Basel) (2014)

Bottom Line: While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites.Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures.The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future.

View Article: PubMed Central - PubMed

Affiliation: Institute of Virology and Immunology, CH-3147 Mittelhaeusern, Switzerland. kenneth.mccullough@vetsuisse.unibe.ch.

ABSTRACT
Dendritic cells (DC) play essential roles determining efficacy of vaccine delivery with respect to immune defence development and regulation. This renders DCs important targets for vaccine delivery, particularly RNA vaccines. While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites. Delivery of mRNA has benefitted from application of cationic entities; these offer value following endocytosis of RNA, when cationic or amphipathic properties can promote endocytic vesicle membrane perturbation to facilitate cytosolic translocation. The present review presents how such advances are being applied to the delivery of a new form of RNA vaccine, replicons (RepRNA) carrying inserted foreign genes of interest encoding vaccine antigens. Approaches have been developed for delivery to DCs, leading to the translation of the RepRNA and encoded vaccine antigens both in vitro and in vivo. Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures. The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future.

No MeSH data available.


Related in: MedlinePlus

Nanoparticulate delivery of the RepRNA is designed to promote efficient uptake into endocytic vesicles, in which the RepRNA can be seen to accumulate. Thereafter, a gradual cytosolic translocation of the RepRNA from the endocytic vesicles, probably promoted by acidification of the vesicles, is essential to ensure delivery of the RepRNA to the intracellular site for RNA translation. It is considered that the acidification process, together with activation of the cellular redox processes facilitated destabilisation of the delivery vehicle and RNA, to permit entry of the ribosomes for translation.
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vaccines-02-00735-f003: Nanoparticulate delivery of the RepRNA is designed to promote efficient uptake into endocytic vesicles, in which the RepRNA can be seen to accumulate. Thereafter, a gradual cytosolic translocation of the RepRNA from the endocytic vesicles, probably promoted by acidification of the vesicles, is essential to ensure delivery of the RepRNA to the intracellular site for RNA translation. It is considered that the acidification process, together with activation of the cellular redox processes facilitated destabilisation of the delivery vehicle and RNA, to permit entry of the ribosomes for translation.

Mentions: An alternative to VRP-based delivery of RepRNA vaccines is application of biodegradable nanoparticulate vehicles (Figure 1), which have shown high potential for delivering to DC [1,24,25]. Replicon RNA has been delivered by coating on to gold microparticles [26], but these are neither biodegradable nor nanoparticles, and do not offer the advantages of biodegradable nanoparticles for targeting DCs and processing via DC endocytic pathways. While mRNA delivery to DCs has proven successful [27,28,29,30,31,32], it has only recently been shown that such nanoparticulate delivery is feasible for the much larger RepRNA molecules [33] (Figure 2 and Figure 3). This success of nanoparticle-based delivery of RepRNA to DCs requires an appreciation of the DC requirements for interaction with the delivery vehicles and the subsequent intracellular delivery of the RepRNA to the RNA translation sites (Figure 3).


Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles.

McCullough KC, Milona P, Thomann-Harwood L, Démoulins T, Englezou P, Suter R, Ruggli N - Vaccines (Basel) (2014)

Nanoparticulate delivery of the RepRNA is designed to promote efficient uptake into endocytic vesicles, in which the RepRNA can be seen to accumulate. Thereafter, a gradual cytosolic translocation of the RepRNA from the endocytic vesicles, probably promoted by acidification of the vesicles, is essential to ensure delivery of the RepRNA to the intracellular site for RNA translation. It is considered that the acidification process, together with activation of the cellular redox processes facilitated destabilisation of the delivery vehicle and RNA, to permit entry of the ribosomes for translation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494254&req=5

vaccines-02-00735-f003: Nanoparticulate delivery of the RepRNA is designed to promote efficient uptake into endocytic vesicles, in which the RepRNA can be seen to accumulate. Thereafter, a gradual cytosolic translocation of the RepRNA from the endocytic vesicles, probably promoted by acidification of the vesicles, is essential to ensure delivery of the RepRNA to the intracellular site for RNA translation. It is considered that the acidification process, together with activation of the cellular redox processes facilitated destabilisation of the delivery vehicle and RNA, to permit entry of the ribosomes for translation.
Mentions: An alternative to VRP-based delivery of RepRNA vaccines is application of biodegradable nanoparticulate vehicles (Figure 1), which have shown high potential for delivering to DC [1,24,25]. Replicon RNA has been delivered by coating on to gold microparticles [26], but these are neither biodegradable nor nanoparticles, and do not offer the advantages of biodegradable nanoparticles for targeting DCs and processing via DC endocytic pathways. While mRNA delivery to DCs has proven successful [27,28,29,30,31,32], it has only recently been shown that such nanoparticulate delivery is feasible for the much larger RepRNA molecules [33] (Figure 2 and Figure 3). This success of nanoparticle-based delivery of RepRNA to DCs requires an appreciation of the DC requirements for interaction with the delivery vehicles and the subsequent intracellular delivery of the RepRNA to the RNA translation sites (Figure 3).

Bottom Line: While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites.Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures.The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future.

View Article: PubMed Central - PubMed

Affiliation: Institute of Virology and Immunology, CH-3147 Mittelhaeusern, Switzerland. kenneth.mccullough@vetsuisse.unibe.ch.

ABSTRACT
Dendritic cells (DC) play essential roles determining efficacy of vaccine delivery with respect to immune defence development and regulation. This renders DCs important targets for vaccine delivery, particularly RNA vaccines. While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites. Delivery of mRNA has benefitted from application of cationic entities; these offer value following endocytosis of RNA, when cationic or amphipathic properties can promote endocytic vesicle membrane perturbation to facilitate cytosolic translocation. The present review presents how such advances are being applied to the delivery of a new form of RNA vaccine, replicons (RepRNA) carrying inserted foreign genes of interest encoding vaccine antigens. Approaches have been developed for delivery to DCs, leading to the translation of the RepRNA and encoded vaccine antigens both in vitro and in vivo. Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures. The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future.

No MeSH data available.


Related in: MedlinePlus