Improved method for synthesis of low molecular weight protamine–siRNA conjugate

Zhili Yu, Junxiao Ye, Xing Pei, Lu Sun, Ergang Liu, Jianxin Wang, Yongzhuo Huang, Seung Jin Lee, Huining He

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides (CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine (LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.

Original languageEnglish
Pages (from-to)116-126
Number of pages11
JournalActa Pharmaceutica Sinica B
Issue number1
StatePublished - Jan 2018

Bibliographical note

Publisher Copyright:
© 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences


  • Biomimetic delivery
  • Cell penetrating peptide
  • Conjugate
  • Conjugation yield
  • Crosslinker
  • siRNA


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