工程化脂质体在大肠杆菌中递送核酸模拟物。

Engineered liposomes to deliver nucleic acid mimics in Escherichia coli.

机构信息

LEPABE - Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal; ALiCE - Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.

出版信息

J Control Release. 2023 Mar;355:489-500. doi: 10.1016/j.jconrel.2023.02.012. Epub 2023 Feb 14.

DOI:10.1016/j.jconrel.2023.02.012

PMID:36775246

Abstract

Antisense oligonucleotides (ASOs) composed of nucleic acid mimics (NAMs) monomers are considered as potential novel therapeutic drugs against bacterial infections. However, bacterial envelopes are generally impermeable to naked oligonucleotides. Herein, liposomes loaded with NAMs-modified oligonucleotides (LipoNAMs) were evaluated to deliver ASOs in Escherichia coli. Specifically, we tested several surface modifications that included methoxyPEG conjugated to different lipid anchors or modification of the PEG distal ends with maleimide groups and antibodies. MethoxyPEG coated LipoNAMs showed low delivery efficiency for most bacteria, but maleimide-functionalized PEG LipoNAMs were able to deliver ASOs to nearly half of the bacterial population. Conjugation of antibodies to maleimide-functionalized PEG LipoNAMs increased 1.3-fold the delivery efficiency, enhancing the selectivity towards E. coli and biocompatibility. This work demonstrated for the first time that the coupling of antibodies to PEGylated liposomes can significantly improve the delivery of ASOs in E. coli, which might bring alternative routes for the treatment of bacterial infections in the future.

摘要

反义寡核苷酸（ASOs）由核酸类似物（NAMs）单体组成，被认为是一种针对细菌感染的潜在新型治疗药物。然而，细菌包膜通常对裸露的寡核苷酸不可渗透。本文中，我们评估了载有 NAMs 修饰的寡核苷酸的脂质体（LipoNAMs）在大肠杆菌中递送 ASO 的效果。具体而言，我们测试了几种表面修饰，包括不同脂质锚接物上的甲氧基聚乙二醇（methoxyPEG）修饰或聚乙二醇（PEG）末端与马来酰亚胺基团和抗体的修饰。甲氧基聚乙二醇（methoxyPEG）包裹的 LipoNAMs 对大多数细菌的递送效率较低，但马来酰亚胺功能化的 PEG LipoNAMs 能够将 ASO 递送到近一半的细菌群体中。将抗体与马来酰亚胺功能化的 PEG LipoNAMs 偶联可将递送效率提高 1.3 倍，增强了对大肠杆菌的选择性和生物相容性。这项工作首次证明，将抗体偶联到聚乙二醇化脂质体上可以显著提高 ASO 在大肠杆菌中的递送效果，这可能为未来治疗细菌感染带来新的途径。