Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma

Jul 9, 2025Journal of controlled release : official journal of the Controlled Release Society

Using low-frequency ultrasound to safely open the brain barrier for delivering RNA nanoparticles to brain tumors

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Abstract

A frequency of 850 kHz and 180 kPa pressure achieved a 10-fold increase in the delivery of lipid nanoparticles (LNPs) containing siRNAs to healthy brains.

Focused ultrasound combined with microbubbles can safely disrupt the blood-brain barrier (BBB) to facilitate drug delivery.
Different frequencies and pressures were tested to optimize conditions for BBB opening, with specific attention to maintaining microvascular integrity.
LNPs containing different ionizable lipids were compared, both showing success in delivering therapeutic agents across the BBB.
In a glioblastoma mouse model, LNPs with siRNAs demonstrated a 6.7-fold increase in fluorescence, indicating effective delivery to tumors.
Microscopy and bioluminescence techniques confirmed significant enhancements in the delivery of both small molecules and LNPs post-treatment.

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Ionizable Lipid Nanoparticles (LNP) 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 focused ultrasound (FUS) 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. Two types of LNPs containing different ionizable lipids (SM-102 and Lipid-14) were compared and both achieved successful brain delivery following FUS-mediated BBB opening. In a glioblastoma syngeneic mouse model, where the BBB remains largely intact under baseline conditions, siRNA-Cy5-LNP was successfully delivered. A frequency of 850 kHz and 180 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 h. 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.

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Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma

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