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Modular Calcium-Responsive and CD9-Targeted Phospholipase System Enhancing Endosomal Escape for DNA Delivery
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DOI：10.1002/advs.202410815.png)
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Abstract
En 中文
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.
Keywords:
calcium-responsive system
CD9 targeting
DNA delivery
endosomal escape
phospholipase C
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