Reversible blood-brain barrier opening utilizing the membrane active peptide melittin in vitro and in vivo

Raleigh M. Linville, Alexander Komin, Xiaoyan Lan, Jackson G. DeStefano, Chengyan Chu, Guanshu Liu, Piotr Walczak, Kalina Hristova, Peter C. Searson

Research output: Contribution to journalArticlepeer-review


The blood-brain barrier (BBB) tightly controls entry of molecules and cells into the brain, restricting the delivery of therapeutics. Blood-brain barrier opening (BBBO) utilizes reversible disruption of cell-cell junctions between brain microvascular endothelial cells to enable transient entry into the brain. Here, we demonstrate that melittin, a membrane active peptide present in bee venom, supports transient BBBO. From endothelial and neuronal viability studies, we first identify the accessible concentration range for BBBO. We then use a tissue-engineered model of the human BBB to optimize dosing and elucidate the mechanism of opening. Melittin and other membrane active variants transiently increase paracellular permeability via disruption of cell-cell junctions that result in transient focal leaks. To validate the results from the tissue-engineered model, we then demonstrate that transient BBBO can be reproduced in a mouse model. We identify a minimum clinically effective intra-arterial dose of 3 μM min melittin, which is reversible within one day and neurologically safe. Melittin-induced BBBO represents a novel technology for delivery of therapeutics into the brain.

Original languageEnglish (US)
Article number120942
StatePublished - Aug 2021


  • Blood-brain barrier
  • Drug delivery
  • Melittin
  • Peptide
  • Tissue engineering

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials


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