Mechanism of endosomal escape by pH -responsive nucleic-acid vectors

Chang, Shih-Min; Yu, Chia Ying; Chen, Yi-Fan

doi:10.1103/physreve.106.034408

Mechanism of endosomal escape by pH -responsive nucleic-acid vectors

Journal Article · Wed Sep 28 00:00:00 EDT 2022 · Physical Review. E

DOI:https://doi.org/10.1103/physreve.106.034408· OSTI ID:1982808

Chang, Shih-Min ^[1]; Yu, Chia Ying ^[1]; Chen, Yi-Fan ^[1]

National Central University, Taoyuan (Taiwan)

Successful intracellular delivery of nucleic acids (NAs) hinges on many factors, one of them being NAs’ efficacious escape from endosomes. As competent NA vectors, pH-responsive gemini surfactants (GSs) might achieve high efficacy by facilitating endosomal escape. However, how the GSs assist the escape remains debated as many proposed mechanisms still lack experimental support, which hinders replication and further improvement of the efficient delivery. Here, via UV, fluorescence spectroscopy, and small-angle neutron scattering (SANS), we examined a pH-responsive GS's and a pH-unresponsive GS's capabilities to compact DNA and withstand binding competition, and their interactions with model endosomal and lysosomal membranes, at varied pHs. Acidification-driven enhancement of DNA-compaction capability and of stability against binding competition were found specific to the pH-responsive GS. Alongside the pH-responsive GS's structural perturbation to the membranes as observed with SANS, the features suggest that pH-responsive GSs facilitate endosomal escape by releasing excess GS molecules from DNA-GS complexes upon acidification in endosome maturation, with the released GS molecules disrupting endosomal and lysosomal membranes and thereby assisting the escape. Here a general design principle for NA vectors is proposed on the basis of this experimental finding.

View Accepted Manuscript (DOE)

Research Organization:: National Central University, Taoyuan (Taiwan); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: Ministry of Science and Technology; National Central University; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1982808

Journal Information:: Physical Review. E, Journal Name: Physical Review. E Journal Issue: 3 Vol. 106; ISSN 2470-0045

Publisher:: American Physical Society (APS)Copyright Statement

Country of Publication:: United States

Language:: English

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Mechanism of endosomal escape by pH -responsive nucleic-acid vectors

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