TY - JOUR
T1 - Intracellular Communication between Synthetic Macromolecules
AU - Evans, Cameron
AU - Ho, Diwei
AU - Marlow, Joshua B.
AU - King, Jessica
AU - Hee, Charmaine
AU - Wong, Lucas
AU - Atkin, Rob
AU - Smith, Nicole
AU - Warr, Gregory
AU - Norret, Marck
AU - Swaminatha, Iyer
PY - 2022/8/10
Y1 - 2022/8/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135768538&partnerID=8YFLogxK
UR - https://www.webofscience.com/wos/woscc/full-record/WOS:000835133900001
U2 - 10.1021/jacs.2c02793
DO - 10.1021/jacs.2c02793
M3 - Article
C2 - 35901278
SN - 0002-7863
VL - 144
SP - 14112
EP - 14120
JO - Journal of the Amercian Chemical Society
JF - Journal of the Amercian Chemical Society
IS - 31
ER -