Overcoming endosomal barrier by amphotericin B-loaded dual pH-responsive PDMA- b-PDPA micelleplexes for siRNA delivery

Haijun Yu, Yonglong Zou, Yiguang Wang, Xiaonan Huang, Gang Huang, Baran D. Sumer, David A. Boothman, Jinming Gao

Research output: Contribution to journalArticlepeer-review

189 Scopus citations


The endosomal barrier is a major bottleneck for the effective intracellular delivery of siRNA by nonviral nanocarriers. Here, we report a novel amphotericin B (AmB)-loaded, dual pH-responsive micelleplex platform for siRNA delivery. Micelles were self-assembled from poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-(diisopropylamino)ethyl methacrylate) (PDMA-b-PDPA) diblock copolymers. At pH 7.4, AmB was loaded into the hydrophobic PDPA core, and siRNA was complexed with a positively charged PDMA shell to form the micelleplexes. After cellular uptake, the PDMA-b-PDPA/siRNA micelleplexes dissociated in early endosomes to release AmB. Live cell imaging studies demonstrated that released AmB significantly increased the ability of siRNA to overcome the endosomal barrier. Transfection studies showed that AmB-loaded micelleplexes resulted in significant increase in luciferase (Luc) knockdown efficiency over the AmB-free control. The enhanced Luc knockdown efficiency was abolished by bafilomycin A1, a vacuolar ATPase inhibitor that inhibits the acidification of the endocytic organelles. These data support the central hypothesis that membrane poration by AmB and increased endosomal swelling and membrane tension by a "proton sponge" polymer provided a synergistic strategy to disrupt endosomes for improved intracellular delivery of siRNA.

Original languageEnglish (US)
Pages (from-to)9246-9255
Number of pages10
JournalACS Nano
Issue number11
StatePublished - Nov 22 2011


  • amphotericin B
  • endosomal escape
  • nonviral nanocarrier
  • pH-responsive micelleplexes
  • polymeric micelles
  • siRNA delivery

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)


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