In vivo assessment of triazine lipid nanoparticles as transfection agents for plasmid DNA.
In vivo assessment of triazine lipid nanoparticles as transfection agents for plasmid DNA.
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DOI：
10.1039/d2bm01289h
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发表时间：
2022-12-06
影响因子：
6.6
通讯作者：
Venditto, Vincent J.
中科院分区：
文献类型：
--
作者：
Nardo, David;Pitts, Michelle G.;Kaur, Rupinder;Venditto, Vincent J.
用于质粒DNA的体内递送的非病毒载体依赖于优化的制剂以实现稳健的转基因表达。已经开发了几种阳离子脂质来递送核酸，但大多数文献都集中在siRNA上，并排除了质粒DNA，其可能具有免疫原性较低的优点。在这项研究中，我们描述了在体内评价的阳离子三嗪基脂质，以前由我们的小组。我们确定了一种具有有限体内毒性的脂质，用于优化脂质制剂的研究，其中包括评价PEG和辅助脂质对转基因表达的影响。然后，我们证明了由三嗪脂质形成的脂质复合物而不是脂质纳米颗粒实现了与AAV载体相似的转基因表达水平，并且与市售阳离子脂质DOTAP相比提供了增强的表达。重要的是，脂质纳米颗粒和脂质复合物诱导针对表达的蛋白质的最小抗体谱，同时充当在直接递送蛋白质时诱导稳健的抗体应答的平台。总的来说，这些数据证明了基于三嗪的脂质作为用于基因递送的非病毒载体的潜力，并强调了基于确切含量优化每种制剂以实现质粒DNA构建体的增强的转基因表达的需要。使用优化的制剂参数在小鼠中评估基于三嗪的脂质的毒性和转染效率，所述优化的制剂参数导致与含有市售阳离子脂质的制剂相比具有显著改善的转基因表达的lipoplex制剂。
Non-viral vectors for in vivo delivery of plasmid DNA rely on optimized formulations to achieve robust transgene expression. Several cationic lipids have been developed to deliver nucelic acids, but most literature has focused on siRNA and excluded plasmid DNA, which may have the advantage of being less immunogenic. In this study, we describe the in vivo evaluation of cationic triazine based lipids, previously prepared by our group. We identify one lipid with limited in vivo toxicity for studies to optimize the lipid formulations, which include an evaluation of the influence of PEG and helper lipids on transgene expression. We then demonstrate that lipoplexes, but not lipid nanoparticles, formed from triazine lipids achieve similar transgene expression levels as AAV vectors and offer enhanced expression as compared to a commercially available cationic lipid, DOTAP. Importantly, the lipid nanoparticles and lipoplexes induce minimal antibody profiles toward the expressed protein, while serving as a platform to induce robust antibody responses when directly delivering the protein. Collectively, these data demonstrate the potential for triazine based lipids as non-viral vectors for gene delivery, and highlights the need to optimize each formulation based on the exact contents to achieve enhanced transgene expression with plasmid DNA constructs. A triazine based lipid was evaluated in mice for toxicity and transfection efficiency using optimized formulation parameters that result in a lipoplex formulation with significantly improved transgene expression as compared to formulations containing commercially available cationic lipids.
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