In a groundbreaking study, Rezai et al. unveiled a promising avenue for treating Alzheimer's disease (AD) using aducanumab and a cutting-edge delivery method1 (Figure 1A). The team employed magnetic resonance-guided focused ultrasound (MRgFUS) to transiently open the blood–brain barrier (BBB), facilitating the transport of the drug from the blood circulation to the brain tissue. This resulted in a remarkable reduction in amyloid deposition in the treated cerebral area in three human patients. The study counters the drug delivery barriers of the brain by demonstrating the potential efficacy of this innovative approach in treating Alzheimer's. Multiple aspects that impact the drug delivery, distribution, penetration, and clearance upon MRgFUS-mediated BBB opening. (A) Schematic illustration of the transcranial MRgFUS and mechanism of action. The helmet-shaped hemispherical phased array is comprised of multiple ultrasound transducers, allowing for electronic steering and beam refocusing through the skull. Intracerebral endothelial cells are shown as FUS beams converge toward the target location, causing circulating MBs within the acoustic field to oscillate. The resulting stable MB oscillation leads to transient opening of the BBB. Systematically administrated therapeutics (e.g., antibody) will be able to pass the opened tight-junction between cells via paracellular pathway and reach to the brain parenchyma. The transport of therapeutics in the parenchyma is regulated by ECS through mainly diffusion. (B) Fluid and matter transport (therapeutics, filaments, proteins and so on) in the brain can be enhanced in ECS (contains an abundance of proteoglycans and hyaluronan, which provide a low-resistance hydraulic conduit that can rapidly expand and shrink in response the physiological, pathological conditions, and external stimulation). With a time period of FUS application to the targeted brain areas, local ECS can be expanded to facilitate the fluid and matter transport, which can contribute to the enhanced benefit of therapeutics when combined with FUS. BBB, blood–brain barrier; ECS, extracellular space; MBs, microbubbles; MRgFUS, magnetic resonance-guided focused ultrasound. MRgFUS stands out as a pivotal modality in brain drug delivery; it offers distinctive advantages, particularly in achieving high spatiotemporal resolution. This technology selectively and reversibly opens the BBB, primarily through the paracellular pathway. This noninvasive methodology presents a compelling approach to increasing the brain parenchyma's permeability to drugs. One key feature lies in the capacity to engineer the volume, shape, and depth of the focal spot in the brain tissue. This engineered precision caters to the specific requirements of treating diverse neurological diseases. The adaptability and precision of MRgFUS open avenues for targeted and efficacious interventions in the intricate landscape of brain-related pathologies. Beyond the anticipated benefits of enhanced aducanumab (an FDA-approved amyloid beta-directed human monoclonal antibody indicated to treat Alzheimer's disease) delivery to the brain, the study implicated the intricate dynamics of drug/toxic complex diffusion and clearance within the human brain parenchyma. Notably, although the scientific discussion around the benefits of aducanumab is ongoing, ultrasound waves not only facilitate BBB opening but also interact with the brain parenchyma beyond the BBB to induce multiple effects2, 3 that could account for the overall benefit (Figure 1B). Considering the importance of the extracellular space (ECS), perivascular space (PVS), and cerebrospinal fluid flow dynamics in modulating drug diffusion, distribution, and waste clearance,4 several questions remain that require further investigation. First, does ultrasound expand the ECS? Second, does it impact the PVS? Third, can ultrasound enhance flow transport, improving the clearance of antibodies and degraded amyloid fragments? Fourth, how does ultrasound interact with brain cells (e.g., neurons, astrocytes, etc.)? Fifth, does any mechanical activation of the signaling pathway have an impact? Finally, how can the technology be translated and extended to increase the efficacy of other treatment modalities enabled by larger particles, such as antibody–drug conjugates, adeno-associated viruses, and lipid nanoparticles? Some of these aspects have been studied in the preclinical animals' modes; for instance, pulsed ultrasound has been shown to expand the ECS and PVS in rodents.5 However, this has not been thoroughly studied in humans. These considerations will open a new frontier, prompting a reevaluation of the multifaceted effects of ultrasound on brain tissue dynamics and elucidating and improving drug delivery to the brain. Expanding our knowledge in this field will enable the treatment of a broad spectrum of brain diseases, including Alzheimer's and many others. Notably, the ultrasound exposures are characterized by brief bursts lasting 5–10 ms. These bursts occur once per second, constituting a total treatment duration of approximately 2 min. Crucially, despite the brevity of these exposures, the peak intensity of the ultrasound wave is exceptionally high. This high-intensity ultrasound can induce changes in the ECS and PVS when penetrating brain tissue. In summary, this scientific breakthrough underscores the potential of ultrasound-mediated drug delivery in revolutionizing Alzheimer's therapy. Further exploration of these mechanisms beyond the BBB promises to refine treatment strategies and pave the way for transformative advancements in the field. Zhenghong Gao: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; validation; visualization; writing – original draft; writing – review & editing. This study is supported by Therapeutic Idea Award (W81XWH2110219) funded by DOD (CDMRP) through Amyotrophic Lateral Sclerosis Research Program. The author declares no conflict of interest in this study. The ethics approval was not needed in this study. Data sharing is not applicable to this article as no new data were created or analyzed in this study.