Combinatorial Library of Cyclic Benzylidene Acetal-Containing pH-Responsive Lipidoid Nanoparticles for Intracellular mRNA Delivery

Bioconjug Chem. 2020 Jul 15;31(7):1835-1843. doi: 10.1021/acs.bioconjchem.0c00295. Epub 2020 Jun 24.


Lipidoid nanoparticles have been demonstrated to be effective for intracellular delivery of small molecule drugs, proteins, and nucleic acids. Stimuli-responsive lipidoid nanoparticles are able to further improve delivery efficacy and reduce carrier-induced toxicity. Our group previously developed reduction and photoresponsive combinatorial libraries of lipidoid nanoparticles for small molecule and biologics delivery. Herein, we describe the synthesis, characterization, and intracellular mRNA delivery application of a new library of pH-responsive lipidoid nanoparticles. The acid-degradable cyclic benzylidene acetal-containing cationic lipidoids (R-O16CBA) were synthesized through a multistep reaction and characterized by NMR and MS. The acid-triggered degradation of lipidoids was studied using NMR, MS, DLS, and TEM. The results revealed that the R-O16CBA lipidoid can be completely degraded at pH 5. The R-O16CBA lipidoid nanoparticles were then fabricated with different formulations of DOPE and cholesterol and tested in vitro for intracellular mRNA delivery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetals / chemistry*
  • Combinatorial Chemistry Techniques*
  • Drug Carriers*
  • Hydrogen-Ion Concentration*
  • Hydrophobic and Hydrophilic Interactions
  • Lipids / chemistry*
  • Microscopy, Electron, Transmission
  • Nanoparticles / chemistry*
  • RNA, Messenger / administration & dosage*
  • Spectrum Analysis / methods


  • Acetals
  • Drug Carriers
  • Lipids
  • RNA, Messenger