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/Subject(The therapeutic and research potentials of oligonucleotides \(ONs\) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs \(SSOs\) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs.)
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/Author(Bost, J., Ojansivu, M., Munson, M. et al)
/Title(Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides)
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doi:10.1038/s42003-022-03132-2
Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides
Jeremy P. Bost
Miina Ojansivu
Michael J. Munson
Emelie Wesén
Audrey Gallud
Dhanu Gupta
Oskar Gustafsson
Osama Saher
Julia Rädler
Stuart G. Higgins
Taavi Lehto
Margaret N. Holme
Anders Dahlén
Ola Engkvist
Per-Erik Strömstedt
Shalini Andersson
C. I. Edvard Smith
Molly M. Stevens
Elin K. Esbjörner
Anna Collén
Samir El Andaloussi
Springer US
Communications Biology, doi:10.1038/s42003-022-03132-2
Springer
2022-02-23T15:30:44+01:00
2022-02-22T06:53:17+05:30
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