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Regulation of Proteins to the Cytosol Using Delivery Systems with Engineered Polymer Architecture.

  • Kretzmann, Jessica A1, 2
  • Luther, David C2
  • Evans, Cameron W1
  • Jeon, Taewon2, 3
  • Jerome, William2
  • Gopalakrishnan, Sanjana2
  • Lee, Yi-Wei2
  • Norret, Marck1
  • Iyer, K Swaminathan1
  • Rotello, Vincent M2
  • 1 School of Molecular Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia. , (Australia)
  • 2 Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, Massachusetts 01003, United States. , (United States)
  • 3 Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, 230 Stockbridge Road., Amherst, Massachusetts 01003, United States. , (United States)
Published Article
Journal of the American Chemical Society
American Chemical Society
Publication Date
Mar 11, 2021
DOI: 10.1021/jacs.1c00258
PMID: 33705125


Intracellular protein delivery enables selective regulation of cellular metabolism, signaling, and development through introduction of defined protein quantities into the cell. Most applications require that the delivered protein has access to the cytosol, either for protein activity or as a gateway to other organelles such as the nucleus. The vast majority of delivery vehicles employ an endosomal pathway however, and efficient release of entrapped protein cargo from the endosome remains a challenge. Recent research has made significant advances toward efficient cytosolic delivery of proteins using polymers, but the influence of polymer architecture on protein delivery is yet to be investigated. Here, we developed a family of dendronized polymers that enable systematic alterations of charge density and structure. We demonstrate that while modulation of surface functionality has a significant effect on overall delivery efficiency, the endosomal release rate can be highly regulated by manipulating polymer architecture. Notably, we show that large, multivalent structures cause slower sustained release, while rigid spherical structures result in rapid burst release.

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