Guanine and cytosine-rich nucleic acid sequences have the potential to form secondary structures such as G-quadruplexes and i-motifs, respectively. We show that stabilisation of G-quadruplexes using small molecules destabilises the i-motifs, and vice versa, indicating these gene regulatory controllers are interdependent in human cells. This has important implications as these structures are predominately considered as isolated structural targets for therapy, but their interdependency highlights the interplay of both structures as an important gene regulatory switch.
Non-viral delivery is an important strategy for selective
and efficient
gene therapy, immunization, and RNA interference, which overcomes
problems of genotoxicity and inherent immunogenicity associated with
viral vectors. Liposomes and polymers are compelling candidates as
carriers for intracellular, non-viral delivery, but maximal efficiencies
of around 1% have been reported for the most advanced non-viral carriers.
Here, we develop a library of dendronized bottlebrush polymers with
controlled defects, displaying a level of precision surpassed only
by biological molecules like DNA, RNA, and proteins. We test concurrent
and competitive delivery of DNA and show for the first time that,
while intracellular communication is thought to be an exclusively
biomolecular phenomenon, such communication between synthetic macromolecular
complexes can also take place. Our findings challenge the assumption
that delivery agents behave as bystanders that enable transfection
by passive intracellular release of genetic cargo and improve upon
coarse strategies in intracellular carrier design lacking control
over polymer sequence, architecture, and composition, leading to a
hit-or-miss outcome. Understanding the communication that takes place
between macromolecules will help improve the design of non-viral delivery
agents and facilitate translation of genome engineering, vaccines,
and nucleic acid-based therapies.
DNA G-quadruplex-stabilising ligands can induce global or specific changes in chromatin accessibility and the transcriptome depending on the targeting specificity of the molecule.
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