Cuboplexes: Topologically Active siRNA Delivery

Hojun Kim, Cecilia Leal

Research output: Contribution to journalArticlepeer-review


RNAi technology is currently experiencing a revival due to remarkable improvements in efficacy and viability through oligonucleotide chemical manipulations and/or via their packaging into nanoscale carriers. At present, there is no FDA-approved system for siRNA technology in humans. The design of the next generation of siRNA carriers requires a deep understanding of how a nanoparticle's physicochemical properties truly impart biological stability and efficiency. For example, we now know that nanoparticles need to be sterically stabilized in order to meet adequate biodistribution profiles. At present, targeting, uptake, and, in particular, endosomal escape are among the most critical challenges impairing RNAi technologies. The disruption of endosomes encompasses membrane transformations (for example, pore formation) that cost significant elastic energy. Nanoparticle size and shape have been identified as relevant parameters impacting tissue accumulation and cellular uptake. In this paper, we demonstrate that the internal structure of lipid-based particles offers a different handle to promote endosomal membrane topological disruptions that enhance siRNA delivery. Specifically, we designed sterically stabilized lipid-based particles that differ from traditional liposomal systems by displaying highly ordered bicontinuous cubic internal structures that can be loaded with large amounts of siRNA. This system differs from traditional siRNA-containing liposomes (lipoplexes) as the particle-endosomal membrane interactions are controlled by elasticity energetics and not by electrostatics. The resulting "PEGylated cuboplex" has the ability to deliver siRNA and specifically knockdown genes with efficiencies that surpass those achieved by traditional lipoplex systems.

Original languageEnglish (US)
Pages (from-to)10214-10226
Number of pages13
JournalACS Nano
Issue number10
StatePublished - Sep 21 2015


  • PEGylated liposomes
  • bicontinuous cubic phases
  • cubosomes
  • liposomes
  • nanomedicine
  • nanoparticles
  • siRNA delivery

ASJC Scopus subject areas

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


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