Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines

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• 作者：Thomas Dé ; moulins ; PhD^a ; ^{thomas.demoulins@ivi.admin.ch" class="auth_mail" title="E-mail the corresponding author} ; Panagiota Milona ; PhD^a ; Pavlos C. Englezou ; PhD^a ; Thomas Ebensen ; PhD^b ; Kai Schulze ; PhD^b ; Rolf Suter ; PhD^a ; ¹ ; Chantal Pichon ; PhD^c ; Patrick Midoux ; PhD^c ; Carlos A. Guzmá ; n ; MD ; PhD^b ; Nicolas Ruggli ; PhD^a ; Kenneth C. McCullough ; PhD^a
• 关键词：Replicon-RNA ; Self-replicating vaccine ; Polyplexes ; Blood dendritic cells ; Intracellular delivery ; Humoral and cellular immunity ; Adjuvant ; Influenza vaccines
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：12
• 期：3
• 页码：711-722
• 全文大小：2128 K

文摘

Self-amplifying replicon RNA (RepRNA) are large molecules (12-14 kb); their self-replication amplifies mRNA template numbers, affording several rounds of antigen production, effectively increasing vaccine antigen payloads. Their sensitivity to RNase-sensitivity and inefficient uptake by dendritic cells (DCs) – absolute requirements for vaccine design – were tackled by condensing RepRNA into synthetic, nanoparticulate, polyethylenimine (PEI)-polyplex delivery vehicles. Polyplex-delivery formulations for small RNA molecules cannot be transferred to RepRNA due to its greater size and complexity; the N:P charge ratio and impact of RepRNA folding would influence polyplex condensation, post-delivery decompaction and the cytosolic release essential for RepRNA translation. Polyplex-formulations proved successful for delivery of RepRNA encoding influenza virus hemagglutinin and nucleocapsid to DCs. Cytosolic translocation was facilitated, leading to RepRNA translation. This efficacy was confirmed in vivo, inducing both humoral and cellular immune responses. Accordingly, this paper describes the first PEI-polyplexes providing efficient delivery of the complex and large, self-amplifying RepRNA vaccines.

From the Clinical Editor

The use of self-amplifying replicon RNA (RepRNA) to increase vaccine antigen payloads can potentially be useful in effective vaccine design. Nonetheless, its use is limited by the degradation during the uptake process. Here, the authors attempted to solve this problem by packaging RepRNA using polyethylenimine (PEI)-polyplex delivery vehicles. The efficacy was confirmed in vivo by the appropriate humoral and cellular immune responses. This novel delivery method may prove to be very useful for future vaccine design.