Blakney Anna K, Zhu Yunqing, McKay Paul F, Bouton Clément R, Yeow Jonathan, Tang Jiaqing, Hu Kai, Samnuan Karnyart, Grigsby Christopher L, Shattock Robin J, Stevens Molly M
Department of Infectious Diseases, Imperial College London, Norfolk Place, London, W2 1PG, U.K.
Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ, U.K.
ACS Nano. 2020 May 26;14(5):5711-5727. doi: 10.1021/acsnano.0c00326. Epub 2020 Apr 20.
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 and . We demonstrate that pABOL enhances protein expression and cellular uptake both intramuscular and intradermal injection compared to commercially available polymers 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.
自扩增RNA（saRNA）疫苗具有高度优势，因为与信使核糖核酸（mRNA）相比，它们能提高蛋白质表达水平，从而将所需剂量降至最低。然而，先前的递送策略是针对小干扰RNA（siRNA）或mRNA进行优化的，由于这些RNA的结构差异，不一定能有效地递送saRNA，因此推动了saRNA递送平台的开发。在此，我们设计了一种名为“pABOL”的可生物还原的线性阳离子聚合物用于saRNA递送，并表明增加其分子量可同时提高体外和体内递送效率。我们证明，与市售聚合物相比，pABOL通过肌肉注射和皮内注射均可提高蛋白质表达水平并促进细胞摄取，且肌肉注射可提供针对流感攻击的完全保护。由于聚合物合成的可扩展性和制剂制备的简便性，我们预计这种聚合物作为saRNA的递送载体在疫苗和治疗方面具有很高的临床可转化性。
