Focused Ultrasound-Mediated Blood-Brain Barrier Opening to Enhance Temozolomide Delivery in Glioblastoma: A Systematic Review of Preclinical and Early Clinical Evidence

Introduction Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults, with persistently poor survival despite chemoradiation and temozolomide (TMZ). Limited intratumoral drug delivery imposed by the blood-brain barrier (BBB), along with intrinsic and acquired resistance mechanisms, constrains TMZ efficacy. Focused ultrasound (FUS)-mediated BBB opening (BBBO) has emerged as a noninvasive strategy to transiently and locally enhance central nervous system drug delivery. Purpose To systematically synthesize preclinical and early clinical evidence evaluating the feasibility, safety, and therapeutic impact of FUS-enhanced TMZ delivery in GBM, and to identify key methodological and translational gaps informing future study design. Methods A systematic search of PubMed, Cochrane Library, ClinicalTrials.gov, Embase, and Scopus was conducted through October 2025. Eligible studies combined FUS-mediated BBBO with systemic TMZ in preclinical GBM models or human patients and reported pharmacologic, therapeutic, or safety outcomes. Results Nine studies (6 preclinical, 3 clinical) met inclusion criteria. All studies employed microbubbles to facilitate BBBO. Preclinical studies consistently demonstrated increased intratumoral TMZ delivery, improved tumor control, and prolonged survival with FUS plus TMZ compared with TMZ alone. Two studies directly quantified enhanced intratumoral drug exposure. Clinical studies demonstrated reproducible, MR-guided BBBO with favorable safety profiles and no procedure-related neurological complications. However, survival and pharmacokinetic endpoints were not evaluated. Conclusion Focused ultrasound-mediated BBBO is a feasible and well-tolerated strategy to augment TMZ delivery in GBM. While preclinical evidence supports enhanced intratumoral drug exposure and therapeutic benefit, clinical efficacy remains unproven. Future studies should prioritize standardized protocols, direct pharmacokinetic validation, and adequately powered trials incorporating molecular stratification and clinically meaningful endpoints.