Lysine-Derived Charge-Altering Releasable Transporters: Targeted Delivery of mRNA and siRNA to the Lungs.
Lysine-Derived Charge-Altering Releasable Transporters: Targeted Delivery of mRNA and siRNA to the Lungs.
复制标题
赖氨酸衍生的电荷改变可释放转运蛋白：将 mRNA 和 siRNA 定向递送至肺部。
DOI：
10.1021/acs.bioconjchem.3c00019
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发表时间：
2023
影响因子：
4.7
通讯作者：
Waymouth,RobertM
中科院分区：
文献类型：
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作者：
Blake,TimothyR;Haabeth,OleAW;Sallets,Adrienne;McClellan,RebeccaL;DelCastillo,TrevorJ;Vilches-Moure,JoseG;Ho,WilsonC;Wender,PaulA;Levy,Ronald;Waymouth,RobertM
将核酸治疗剂靶向递送到肺部可以改变肺部疾病的治疗选择。我们先前已经开发了用于体内mRNA转染的寡聚电荷改变可释放转运蛋白（CART），并证明了其用于基于mRNA的癌症疫苗接种和针对小鼠肿瘤的局部免疫调节治疗的功效。虽然我们先前报道的基于甘氨酸的CART-mRNA复合物（G-CART/mRNA）在脾脏中显示出选择性蛋白质表达（小鼠，>99%），但在此，我们报道了一种新的赖氨酸衍生的CART-mRNA复合物（K-CART/mRNA），其在没有添加剂或靶向配体的情况下，在全身IV施用后在肺中显示出选择性蛋白质表达（小鼠，>90%）。我们进一步表明，通过使用K-CART递送siRNA，我们可以显著降低肺定位报告蛋白的表达。血液化学和器官病理学研究表明K-CART是安全的，耐受性良好。本文报道了以简单氨基酸和脂类为原料，采用两步有机催化合成功能化聚酯和低聚碳酸酯-共-α-氨基酯K-CART的新方法。通过对CART结构进行简单的模块化改变来选择性地在脾或肺中指导蛋白质表达的能力从根本上为研究和基因治疗开辟了新的机会。
Targeted delivery of nucleic acid therapeutics to the lungs could transform treatment options for pulmonary disease. We have previously developed oligomeric charge-altering releasable transporters (CARTs) for in vivo mRNA transfection and demonstrated their efficacy for use in mRNA-based cancer vaccination and local immunomodulatory therapies against murine tumors. While our previously reported glycine-based CART-mRNA complexes (G-CARTs/mRNA) show selective protein expression in the spleen (mouse, >99%), here, we report a new lysine-derived CART-mRNA complex(K-CART/mRNA)that, without additives or targeting ligands, shows selective protein expression in the lungs (mouse, >90%) following systemic IV administration. We further show that by delivering siRNA using theK-CART, we can significantly decrease expression of a lung-localized reporter protein. Blood chemistry and organ pathology studies demonstrate thatK-CARTsare safe and well-tolerated. We report on the new step economical, organocatalytic synthesis (two steps) of functionalized polyesters and oligo-carbonate-co-α-aminoesterK-CARTsfrom simple amino acid and lipid-based monomers. The ability to direct protein expression selectively in the spleen or lungs by simple, modular changes to the CART structure opens fundamentally new opportunities in research and gene therapy.