Modular Calcium-Responsive and CD9-Targeted Phospholipase System Enhancing Endosomal Escape for DNA Delivery

被引：0

作者：

Klipp, Alexander ^{[1
]}

Greitens, Christina ^{[1
]}

Scherer, David ^{[1
]}

Elsener, Alexander ^{[1
]}

Leroux, Jean-Christophe ^{[1
]}

Burger, Michael ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Vladimir Prelog Weg 3, CH-8093 Zurich, Switzerland

来源：

ADVANCED SCIENCE | 2025年

基金：

欧洲研究理事会;

关键词：

calcium-responsive system; CD9; targeting; DNA delivery; endosomal escape; phospholipase C; INTRACELLULAR TRAFFICKING; PROTEIN; BAF; COMPLEMENTATION; PATHOGENESIS; VECTORS; KINASES; SIRNA;

D O I：

10.1002/advs.202410815

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Gene delivery systems must overcome multiple barriers, with endosomal escape representing a prominent obstacle. This work has previously shown that a bacterial phospholipase C (PLC) enabled endosomal escape of a non-viral protein-based DNA delivery system termed TFAMoplex. Building upon this, this work introduces a calcium-responsive system designed to enhance endosomal escape through non-covalent capturing of PLC to the TFAMoplex followed by its release within endosomes and nanobody-mediated targeting to the endosomal membrane. This approach leads to improved TFAMoplexes enabling transfection of HeLa cells in full serum with a half maximal effective concentration (EC50) of less than 200 ng DNA per mL serum, using only 5 nM PLC. Particularly, the modular capture, release and targeting system could potentially be adapted to other delivery agents previously constrained by poor endosomal escape. These findings present a promising strategy to achieve efficient endosomal escape, offering prospects for improved delivery of macromolecules, in particular nucleic acids.

引用

页数：14