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Opening the Barrier: Focused Ultrasound for Improved Brain Drug Delivery

Writer: Julia Lanfersieck

Editor: Emily DiMaulo-Milk

Diseases of the brain are often among the most challenging to treat. This is in large part because of the blood-brain barrier (BBB), a protective layer which restricts the passage of substances from the bloodstream into the brain.

Neurons, the primary functional cells of the brain, form complex networks that communicate to regulate nearly all bodily processes including sensation, movement, cognition, and behavior. Neurons can be as long lived as the organism itself, but they have limited capacity for repair and regeneration, making them particularly vulnerable to damage. The BBB serves to shield fragile neurons from toxins, infectious agents, and other blood-borne stressors. However, this barrier also presents a significant obstacle for administering targeted therapeutics, as many compounds are unable to effectively cross into the brain.

Focused ultrasound (FUS) is an actively evolving therapeutic approach that has promise to overcome the difficulty in crossing the BBB. This could significantly enhance the ability of medications to enter into the brain and improve patient outcomes.

A Barrier to Brain Medicine

A major limitation when delivering drugs to the brain is the difficulty of crossing the BBB. The BBB is composed of a layer of tight-junction-associated endothelial cells lining brain blood vessels, together with supporting cells and transport systems that carefully control exchange between the blood and the brain1. Small molecules, such as oxygen, can passively diffuse across this barrier. Lipid-soluble compounds, such as alcohol and caffeine, can also cross the BBB. However, the vast majority of compounds, especially large molecules, are unable to enter the brain because they cannot pass between these tightly sealed cells and are not readily transported across the BBB2.

Consequently, treatments for brain conditions administered orally or intravenously typically fail to adequately penetrate the brain. Increasing the dose can sometimes raise brain exposure modestly, but this approach is limited and can substantially increase systemic side effects and treatment cost. For many neurological disorders, the BBB remains one of the most persistent barriers to effective therapy.

Figure 1. Schematic of the blood-brain barrier (BBB). Created in BioRender. Lanfersieck, J. (2026) https://BioRender.com/qh6t9ck

A New Way Through with Focused Ultrasound

A potential strategy to improve the passage of drugs across the BBB is focused ultrasound (FUS). FUS is the direct application of ultrasonic sound waves which deliver energy to a specific location within the body3. This can remove tissue to create a lesion, a process known as ablation. This technique was first published in 1955 by William and Francis Fry, who used FUS to selectively and precisely ablate a 2- to 3-microm region of the brain without damaging surrounding tissues4.

Over the following decades, technological advances refined FUS techniques, leading to its clinical application. In 2016, the FUS was approved by the FDA for the first time for its application to essential tremor, a neurological disorder causing involuntary shaking5,6. For this one-time procedure, magnetic resonance imaging (MRI) is performed to identify the brain regions responsible for the tremor, and FUS is applied to ablate the target region with high precision. Clinical follow-up studies have shown great benefit, with 100% of patients experiencing an immediate reduction in symptoms and reports estimating 73% improvement of symptoms even after 5 years7.8.

While high-intensity FUS for tissue ablation has proven efficacious, recent innovations have described the use of low-intensity FUS, which preserves tissue integrity, with exciting results. Current uses of FUS are explained further in Table 1.

FUS IntensityPrimary Use MechanismClinical Status
High intensityTissue ablationDelivers concentrated ultrasonic energy to heat and destroy targeted tissue, creating a precise lesionFDA approved for essential tremor, Parkinson’s disease-related tremor, and certain cancers9,10
Low intensityBBB openingUsed with intravenously administered microbubbles to disrupt the BBB temporarily and locally, allowing therapeutics to enter brain tissueIn clinical trials and active preclinical development for improved drug delivery to the brain
NeuromodulationApplies lower-energy ultrasound to alter neural circuit activity without destroying tissueOngoing preclinical and early clinical research for application to addiction, depression, and other neuropsychiatric disorders11

Table 1. Use, mechanism, and clinical status of current focused ultrasound (FUS) applications.

FUS for Opening the Barrier

With low intensity FUS, tissue vibrates, but is not destroyed. This distinction led Dr. Kullervo Hynynen to propose that this technique could be applied to disrupt the BBB12. Building on this idea, Dr. Hyneynen’s lab developed an approach to disrupt the BBB using microbubbles. Microbubbles are tiny gas-filled lipid spheres that expand and contract under ultrasonic energy. When ultrasound is applied at specific frequencies and intensities, the microbubbles oscillate, exerting mechanical stress on the endothelial lining of the vasculature and causing temporary separation of tight junctions13,14. This disrupts the integrity of the BBB and creates openings big enough for drug molecules to pass through into the brain13. Importantly, FUS-mediated BBB opening is reversible, as the BBB reseals within 24 to 48 hours, reducing concerns about long-term effects and fostering confidence in the safety of this technology15.

FUS-mediated BBB disruption is also precise. In clinical applications, MRI-guided brain targeting is used to direct the ultrasound to the specific BBB region of interest. Microbubbles and the therapeutic drug are then co-administered intravenously and circulate through the vasculature. The drug is only able to cross the BBB at the precise location where FUS is applied. The specific frequency and intensity of the ultrasound are carefully optimized to maximize drug delivery while minimizing tissue damage. Further research is needed to refine these settings for different clinical scenarios, but early applications of FUS appear promising.

Figure 2. Schematic of focused ultrasound (FUS) combined with microbubbles to disrupt the blood-brain barrier (BBB). Ultrasound waves induce expansion and contraction of microbubbles in the bloodstream, disrupting the integrity of endothelial cell tight junctions and enabling the delivery of drug particles across the BBB. Created in BioRender. Lanfersieck, J. (2026) https://BioRender.com/qh6t9ck

Applying FUS toward Alzheimer’s disease

FUS treatment is currently being investigated across a range of medical disorders and is believed to have particularly strong potential in treating Alzheimer’s disease (AD). AD is the most common neurodegenerative disorder, affecting over 50 million people worldwide and ranking as the sixth leading cause of death in the United States16. AD is characterized by progressive brain atrophy associated with the accumulation of tau and amyloid-β pathology. Symptoms include memory loss, cognitive decline, and broader behavioral and mood changes17. Despite its high prevalence and decades of research, there still is no cure for AD, and available treatments remain limited.

A central challenge in developing AD treatments is the effective delivery of large molecules, like therapeutic antibodies or viral vectors, across the BBB. FUS-mediated BBB opening offers a direct solution to this limitation.

Preclinical studies first established the versatility of this approach across multiple pathological targets. In mouse models, FUS-mediated BBB opening enhanced the delivery and efficacy of both anti-amyloid and anti-tau antibodies, demonstrating that FUS is not restricted to a single disease mechanism but can be broadly applied to the major drivers of AD pathology18-21. Notably, the ability to improve delivery of anti-tau therapeutics highlights the potential of FUS to support emerging treatment strategies beyond more established amyloid-focused approaches.

Clinical studies have begun to translate these findings to human patients. In a small-scale clinical trial led by Dr. Ali Rezai, FUS combined with microbubbles enhanced drug delivery to the brain and increased accumulation of the anti-amyloid therapy Aducanumab compared to drug administration, indicating potential for this approach to improve therapeutic outcomes in patients15,22,23. Although Aducanumab is now discounted, ongoing studies are evaluating FUS in combination with newer approved anti-amyloid therapies, including Lecanemab and Donanemab. These agents have demonstrated modest clinical efficacy in reducing amyloid burden and slowing cognitive decline on their own; however, FUS-mediated BBB opening may further enhance their therapeutic impact by improving brain penetration and target engagement24,25.

As BBB permeability becomes increasingly addressable through technologies such as FUS, a critical remaining challenge is maximizing the efficacy of therapeutics once they reach the brain. This shift emphasizes the need to optimize target engagement, dosing strategies, and downstream biological effects to achieve meaningful disease modification in AD and other brain disorders.

Broader Implications and Future Directions

The potential applications for FUS-mediated BBB opening extend well beyond AD. Preclinical and clinical research evaluating FUS spans brain tumors, neurodegenerative diseases, and psychiatric conditions13,26-29. By enabling localized and transient BBB modulation, FUS provides a flexible platform for improving the delivery of diverse therapeutic modalities, including antibodies, vectors for gene therapy, and small molecules.

Beyond therapeutics, FUS may also enable new diagnostic and monitoring approaches. BBB opening is bidirectional, meaning molecules can both be delivered to and released from the brain30. In this context, post-FUS peripheral blood sampling could enable “liquid biopsy,” offering a minimally invasive strategy to monitor brain-derived biomarkers, such as amyloid levels, over the course of treatment31,32. While still an emerging approach requiring further refinement, FUS has the potential to enhance current biomarker sampling methods.

Research into FUS is rapidly expanding. Over the last two decades, the Focused Ultrasound Foundation has supported more than 70 clinical trials and several preclinical trials aimed at advancing the clinical translation and refinement of this technology33. Current work focuses on evaluating and improving the safety and precision of repeated BBB opening for long-term clinical use34. Taken together, these advances position FUS-mediated BBB opening as a promising and adaptable platform, with continued optimization of safety, precision, and therapeutic integration remaining essential for its successful clinical translation.

Conclusion

The blood-brain barrier (BBB) is essential for protecting sensitive neurological tissue, but it is also a critical obstacle in the treatment of neurological diseases. However, low-intensity focused ultrasound (FUS) provides a controlled, non-invasive approach that transiently overcomes this barrier, which could be applied across a variety of diseases and therapeutic modalities.

With FDA-approved implications recently established for Parkinson’s disease and essential tremor, high-intensity FUS is already demonstrating clinical impact. With continued research, more FUS-based strategies may be approved in the near future, paving the way for significant improvements in the treatment of neurological diseases.

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