信使 RNA (mRNA) 正在彻底改变包括神经系统疾病在内的多种疾病治疗的未来。脂质制剂已被证明是用于 mRNA 递送的有效平台技术，并且是批准的 mRNA 疫苗的基础。在许多这些脂质制剂中，聚乙二醇 (PEG) 功能化脂质提供空间稳定性，因此在提高离体和体内稳定性方面起着关键作用。然而，对聚乙二醇化脂质的免疫反应可能会损害这些脂质在某些应用中的使用（例如，抗原特异性耐受的诱导），或在敏感组织内（例如, 中枢神经系统 (CNS))。关于这个问题，在本研究中，研究了基于聚肌氨酸 (pSar) 的脂质聚合物作为 mRNA 脂质复合物中 PEG 脂质的替代品，用于控制脑内蛋白表达。合成了四种具有确定肌氨酸平均分子量 (M n  = 2 k、5 k) 和锚二酰基链长度 (m = 14、18) 的聚肌氨酸脂质，并将其掺入阳离子脂质体中。我们发现 pSar 脂质的含量、pSar 链长和碳尾长度决定转染效率和生物分布。增加 pSar 脂质的碳二酰基链长度导致体外蛋白质表达降低 4 倍和 6 倍. 当pSar链或脂碳尾的长度增加时，转染效率降低而循环时间延长。含有 2.5% C14-pSar2k 的 mRNA lipoplexes 通过脑室内注射导致斑马鱼胚胎大脑中最高的 mRNA 翻译，而 C18-pSar2k-脂质体在全身给药后显示出与 DSPE-PEG2k-脂质体相当的循环。总之，pSar-lipid 可实现高效的 mRNA 递送，并且可以替代脂质制剂中的 PEG-脂质以控制 CNS 内的蛋白质表达。

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Messenger RNA (mRNA) is revolutionizing the future of therapeutics in a variety of diseases, including neurological disorders. Lipid formulations have shown to be an effective platform technology for mRNA delivery and are the basis for the approved mRNA vaccines. In many of these lipid formulations, polyethylene glycol (PEG)-functionalized lipid provides steric stabilization and thus plays a key role in improving the stability both ex vivo and in vivo. However, immune responses towards PEGylated lipids may compromise the use of those lipids in some applications (e.g., induction of antigen specific tolerance), or within sensitive tissues (e.g., central nervous system (CNS)). With respect to this issue, polysarcosine (pSar)-based lipopolymers were investigated as an alternative to PEG-lipid in mRNA lipoplexes for controlled intracerebral protein expression in this study. Four polysarcosine-lipids with defined sarcosine average molecular weight (Mn = 2 k, 5 k) and anchor diacyl chain length (m = 14, 18) were synthesized, and incorporated into cationic liposomes. We found that the content, pSar chain length and carbon tail lengths of pSar-lipids govern the transfection efficiency and biodistribution. Increasing carbon diacyl chain length of pSar-lipid led up to 4- and 6-fold lower protein expression in vitro. When the length of either pSar chain or lipid carbon tail increased, the transfection efficiency decreased while the circulation time was prolonged. mRNA lipoplexes containing 2.5% C14-pSar2k resulted in the highest mRNA translation in the brain of zebrafish embryos through intraventricular injection, while C18-pSar2k-liposomes showed a comparable circulation with DSPE-PEG2k-liposomes after systemic administration. To conclude, pSar-lipid enable efficient mRNA delivery, and can substitute PEG-lipids in lipid formulations for controlled protein expression within the CNS.