Accelerated Endosomal Escape of Splice-Switching Oligonucleotides Enables Efficient Hepatic Splice Correction.

ABSTRACT: Splice-switching oligonucleotides (SSOs) can restore protein functionality in pathologies and are promising tools for manipulating the RNA-splicing machinery. Delivery vectors can considerably improve SSO functionality in vivo and allow dose reduction, thereby addressing the challenges of RNA-targeted therapeutics. Here, we report a biocompatible SSO nanocarrier, based on redox-responsive disulfide cross-linked low-molecular-weight linear polyethylenimine (cLPEI), for overcoming multiple biological barriers from subcellular compartments to en-route serum stability and finally in vivo delivery challenges. Intracellularly responsive cross-links of cLPEI significantly accelerated the endosomal escape and offered efficient SSO release to the cell's nucleus, thereby leading to high splice corre

SUBMITTER: Weiss S 

PROVIDER: S-EPMC11826512 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature