Ultrasonic modulation of brain glymphatic transport: from observations to theranostic applications

The glymphatic system in the brain controls the cerebrospinal fluid (CSF) circulation and metabolic waste clearance, which is crucial for understanding the mechanisms and therapeutic opportunities of various brain pathologies. With the rapidly growing interest in its relationship with neurodegenerative conditions, including Alzheimer's disease, its underlying processes are still not fully understood and remain under active investigation. A representative finding is that the glymphatic flow is passively driven by factors such as vascular pulsation, and studies have been conducted to modulate the glymphatic system using external stimuli to enhance waste clearance or to leverage CSF pathways for delivering chemotherapeutic agents. Particularly, glymphatic flow modulation holds great potential for improving drug delivery to the brain via intrathecal administration as an alternative to conventional systemic delivery, which is restricted by the blood-brain barrier (BBB). This review focuses on ultrasound (US) techniques for glymphatic system modulation, with the aim of augmenting glymphatic flow and ultimately improving drug delivery for brain cancer therapy. Given the limited number of cancer-related studies in the field, we comprehensively review US-based glymphatic modulation research to date and identify their implications and future opportunities for brain cancer applications.