Lipid-based nanocarriers have demonstrated high interest in delivering genetic material, exemplified by the success of Onpattro and COVID-19 vaccines. While PEGylation imparts stealth properties, it hampers cellular uptake and endosomal escape, and may trigger adverse reactions like accelerated blood clearance (ABC) and hypersensitivity reactions (HSR). This work highlights the great potential of amphiphilic poly(N-methyl-N-vinylacetamide) (PNMVA) derivatives as alternatives to lipid-PEG for siRNA delivery. PNMVA compounds with different degrees of polymerization and hydrophobic segments, are synthesized. Among them, DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine)-PNMVA efficiently integrates into lipoplexes and LNP membranes and prevents protein corona formation around these lipid carriers, exhibiting stealth properties comparable to DSPE-PEG. However, unlike DSPE-PEG, DSPE-PNMVA₂₄ shows no adverse impact on lipoplexes cell uptake and endosomal escape. In in vivo study with mice, DSPE-PNMVA₂₄ lipoplexes demonstrate no liver accumulation, indicating good stealth properties, extended circulation time after a second dose, reduced immunological reaction, and no systemic pro-inflammatory response. Safety of DSPE-PNMVA₂₄ is confirmed at the cellular level and in animal models of zebrafish and mice. Overall, DSPE-PNMVA is an advantageous substitute to DSPE-PEG for siRNA delivery, offering comparable stealth and toxicity properties while improving efficacy of the lipid-based carriers by minimizing the dilemma effect and reducing immunological reactions, meaning no ABC or HSR effects.

中文翻译：

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聚（N-甲基-N-乙烯基乙酰胺）：用于递送 siRNA 的脂质纳米载体的 PEG 的有力替代品

基于脂质的纳米载体在传递遗传物质方面表现出了浓厚的兴趣，Onpattro 和 COVID-19 疫苗的成功就是例证。虽然聚乙二醇化具有隐形特性，但它会阻碍细胞摄取和内体逃逸，并可能引发不良反应，如加速血液清除 (ABC) 和超敏反应 (HSR)。这项工作凸显了两亲性聚（N-甲基-N-乙烯基乙酰胺）（PNMVA）衍生物作为脂质-PEG 替代品用于 siRNA 递送的巨大潜力。合成了具有不同聚合度和疏水链段的PNMVA化合物。其中，DSPE（1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺）-PNMVA可有效整合到脂质复合物和LNP膜中，并防止这些脂质载体周围形成蛋白质电晕，表现出与DSPE-PEG相当的隐形特性。然而，与 DSPE-PEG 不同，DSPE-PNMVA ₂₄对脂质复合物细胞摄取和内体逃逸没有不利影响。在小鼠体内研究中，DSPE-PNMVA ₂₄ lipoplexs 没有在肝脏中积聚，表明具有良好的隐形特性，延长了第二次给药后的循环时间，减少了免疫反应，并且没有全身促炎症反应。 DSPE-PNMVA ₂₄的安全性在细胞水平以及斑马鱼和小鼠动物模型中得到证实。总体而言，DSPE-PNMVA 是用于 siRNA 递送的 DSPE-PEG 的有利替代品，具有相当的隐形性和毒性特性，同时通过最大限度地减少困境效应和减少免疫反应来提高脂质载体的功效，这意味着没有 ABC 或 HSR 效应。