Big Is Beautiful: Enhanced saRNA Delivery and Immunogenicity by a Higher Molecular Weight, Bioreducible, Cationic Polymer

被引：127

作者：

Blakney, Anna K. ^{[1
]}

Zhu, Yunqing ^{[2
,4
]}

McKay, Paul F. ^{[1
]}

Bouton, Clement R. ^{[1
]}

Yeow, Jonathan ^{[2
]}

Tang, Jiaqing ^{[2
]}

Hu, Kai ^{[1
]}

Samnuan, Karnyart ^{[1
]}

Grigsby, Christopher L. ^{[3
]}

Shattock, Robin J. ^{[1
]}

Stevens, Molly M. ^{[2
,3
]}

机构：

[1] Imperial Coll London, Dept Infect Dis, London W2 1PG, England

[2] Imperial Coll London, Dept Mat, Dept Bioengn, Inst Biomed Engn, London SW7 2AZ, England

[3] Karolinska Inst, Dept Med Biochem & Biophys, S-17165 Stockholm, Sweden

[4] Tong & Univ, Sch Mat Sci & Engn, Shanghai 200092, Peoples R China

来源：

ACS NANO | 2020年 / 14卷 / 05期

基金：

瑞典研究理事会; 英国工程与自然科学研究理事会; 英国惠康基金; 英国医学研究理事会; 欧盟地平线“2020”;

关键词：

RNA; replicon; polymer; vaccine; nucleic acid; influenza; HEMAGGLUTINATION INHIBITION ASSAY; MESSENGER-RNA VACCINES; POLY(AMIDO AMINE)S; DISULFIDE LINKAGES; SYSTEMIC DELIVERY; NONVIRAL DELIVERY; IMMUNE-RESPONSES; IN-VIVO; INFLUENZA; CHALLENGES;

D O I：

10.1021/acsnano.0c00326

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Self-amplifying RNA (saRNA) vaccines are highly advantageous, as they result in enhanced protein expression compared to mRNA (mRNA), thus minimizing the required dose. However, previous delivery strategies were optimized for siRNA or mRNA and do not necessarily deliver saRNA efficiently due to structural differences of these RNAs, thus motivating the development of saRNA delivery platforms. Here, we engineer a bioreducible, linear, cationic polymer called "pABOL" for saRNA delivery and show that increasing its molecular weight enhances delivery both in vitro and in vivo. We demonstrate that pABOL enhances protein expression and cellular uptake via both intramuscular and intradermal injection compared to commercially available polymers in vivo and that intramuscular injection confers complete protection against influenza challenge. Due to the scalability of polymer synthesis and ease of formulation preparation, we anticipate that this polymer is highly clinically translatable as a delivery vehicle for saRNA for both vaccines and therapeutics.

引用

页码：5711 / 5727

页数：17

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