Intracellular Communication between Synthetic Macromolecules

Cameron Evans, Diwei Ho, Joshua B. Marlow, Jessica King, Charmaine Hee, Lucas Wong, Rob Atkin, Nicole Smith, Gregory Warr, Marck Norret, Iyer Swaminatha

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)14112-14120
Number of pages9
JournalJournal of American Chemical Society
Volume144
Issue number31
DOIs
Publication statusPublished - 10 Aug 2022

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