Redox-responsive, reversibly-crosslinked thiolated cationic helical polypeptides for efficient siRNA encapsulation and delivery

Nan Zheng, Ziyuan Song, Yang Liu, Rujing Zhang, Ruoyan Zhang, Catherine Yao, Fatih M. Uckun, Lichen Yin, Jianjun Cheng

Research output: Contribution to journalJournal articleResearchpeer-review


Cationic helical polypeptides, although highly efficient for inducing membrane penetration, cannot stably condense siRNA molecules via electrostatic interactions, which greatly limit the gene knockdown efficiency. By developing and crosslinking the thiolated polypeptide via formation of disulfide bonds post formation of the polypeptide/siRNA complexes, we were able to obtain stable complexes without compromising the helical secondary structure as well as the membrane activity of the polypeptide. As such, the stable polypeptide/siRNA complex was able to notably protect the siRNA cargo from nuclease digestion in the extracellular environment, while the functions of the polypeptide/siRNA complex for effective cellular internalization and endosomal escape are still largely preserved. Because the disulfide is susceptible to cleavage in response to intracellular redox triggers, siRNA release from the complex is expected upon redox triggering by glutathione (GSH) intracellularly and was actually observed upon redox triggers mediated by glutathione (GSH). With the collective contribution of the potent membrane activity and redox-responsive cargo release profiles, the crosslinked complexes enable efficient gene silencing without appreciable cytotoxicity, thus providing a potential strategy for polypeptide-based intracellular siRNA delivery. (C) 2015 Elsevier B.V. All rights reserved.
Original languageEnglish
JournalJournal of Controlled Release
Pages (from-to)231-239
Number of pages9
Publication statusPublished - 2015
Externally publishedYes


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