PROJECT SUMMARY/ABSTRACT There is an unmet critical need for techniques that achieve noninvasive molecular diagnosis of brain tumors. Our group is addressing this unmet need by introducing and developing the focused ultrasound (FUS)-enabled blood-based liquid biopsy technique, which we call sonobiopsy. NIH/NIBIB support (R01EB030102, funding period 8/1/2020–4/30/2024) allowed us to demonstrate the effectiveness and safety of sonobiopsy in mouse and pig models of glioblastoma, the most common primary brain tumor in adults. We also developed a clinical sonobiopsy device by integrating a single-element FUS transducer with a neuronavigation system. These breakthroughs led to our first-in-human clinical study, which demonstrated the initial feasibility and safety of sonobiopsy in patients with glioblastoma. In much the same way that MRI transformed the diagnostic capabilities of neurologic disease by providing anatomic and functional information, sonobiopsy has the potential to provide equally important and complementary molecular information about the brain that is not currently available. Sonobiopsy will be a platform technology that can be applied to the diagnosis and monitoring of various neurological diseases. The objective of this renewal application is to develop and validate a next-generation FUS device called sonocap, which will radically advance the clinical translation of sonobiopsy and enable its broad adoption. The sonocap device is patient-friendly, easily manufactured, accurate in tumor targeting, and safe. We will achieve this objective through two specific aims: Aim 1 will design and construct the wearable sonocap, and Aim 2 will validate the performance and safety of the sonocap in non-human primates (NHPs). The proposed sonocap is significant because it is a breakthrough FUS device that enhances our technical capability in interfacing with the brain using ultrasound, addresses a critical barrier to advancing the clinical translation of sonobiopsy, and improves the clinical practice in the diagnosis and monitoring of brain diseases through sonobiopsy. Our multidisciplinary team has expertise in ultrasound engineering, wearable device design, NHP research, and neurosurgery, and will advance sonocap through the development phase and into future clinical trials. This study has three main innovations: (1) sonobiopsy is a groundbreaking approach for interrogating the brain; (2) the wearable sonocap significantly departs from the status quo in the design of clinical FUS devices; (3) the proposed approach for developing the sonocap combines human head phantom testing and NHP validation. The project outcomes are expected to significantly impact the medical ultrasound field by driving the development of wearable FUS devices, collecting essential large animal data required for clinical translation, and ultimately achieving personalized patient care through noninvasive molecular diagnosis of brain tumors.