Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma
Open accessAbstract
Ionizable Lipid Nanoparticles (LNPs) are an FDA-approved non-viral RNA delivery system, though their use for brain therapy is restricted by the blood-brain barrier (BBB). Focused ultrasound combined with microbubbles can disrupt the BBB, but delivering large particles requires balancing increased peak negative pressures while maintaining microvascular integrity. Herein, we optimized low-frequency ultrasound parameters to induce high-amplitude microbubble oscillations, enabling the safe delivery of LNPs across the BBB. First, BBB opening was assessed at different frequencies (850, 250, and 80 kHz) and pressures by monitoring the extravasation of Evans blue (~1 kDa). Next, the delivery of 4, 70, and 150 kDa Dextrans, LNPs entrapping Cy5-siRNAs (~70 nm in diameter), and LNPs entrapping mRNA (~100 nm in diameter) was evaluated via microscopy and bioluminescence. In a glioblastoma syngeneic mouse model, siRNA-Cy5-LNP was successfully delivered. A frequency of 850 kHz and 125 kPa pressure induced safe BBB opening, enabling delivery of both small molecules and LNPs. In healthy brains, LNP entrapping siRNAs delivery increased 10-fold compared to controls, and LNPs with mRNAs showed a 12-fold increase in bioluminescence after 24 hours. In glioblastoma tumors, LNPs with siRNAs delivery resulted in a 6.7-fold increase in fluorescence. This study paves the way for non-invasive LNP delivery to the brain, offering a versatile platform for brain therapies. TOC graphic:
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- Elbaz, M., Ad-El, N., Chulanova, Y., Brier, D., Goldsmith, M., Bismuth, M., Brosque, A., Sher, D., Gutkin, A., Bar-On, D., Friedman-Morvinski, D., Peer, D., & Ilovitsh, T.
- Affiliations
- The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Laboratory of Precision NanoMedicine, The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978 Israel
- Tel Aviv University (IL)
- Teva Pharmaceuticals (Israel) (IL)
- Corresponding author
- Ilovitsh, Tali
- Venue
- Journal of Controlled Release
- Publisher
- openRxiv
- Published
- 2025-01-26
- Volume
- 385
- Pages
- 114018-114018
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W4412084979
- Cited by
- 28
- References
- 77
- Citations by year
- 2026: 20 · 2025: 8
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
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- Journal of Controlled Release (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- blood-brain barrier opening, ionizable lipid nanoparticles, RNA delivery, glioblastoma, microbubbles, siRNA, mRNA, ultrasonic frequency, acoustic pressure, SM-102, syngeneic mouse model
- MeSH terms
- Ultrasonic Waves, Animals, Blood-Brain Barrier, Brain Neoplasms, Female, Glioblastoma, Humans, Lipids, Liposomes, RNA, Messenger, Gene Transfer Techniques, RNA, Small Interfering, Microbubbles, Cell Line, Tumor, Mice, Nanoparticles
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