Focused Ultrasound-Mediated Blood–Brain Barrier Opening for Enhanced Drug Delivery in Diffuse Gliomas: A Systematic Review

Background/Objectives: The blood–brain barrier (BBB) severely limits the intratumoral delivery of systemically administered therapeutics in diffuse gliomas, including glioblastoma (GBM), contributing to the persistently poor prognosis of these tumors. Focused ultrasound (FUS) combined with microbubble agents enables transient, spatially targeted, and reversible BBB opening (BBBO), offering a non-invasive strategy to enhance drug delivery in this setting. Despite a rapidly growing body of clinical evidence, a systematic synthesis of outcomes across FUS platforms, drug regimens, and study designs is currently lacking. This systematic review aims to critically appraise the available clinical evidence on FUS-mediated BBBO for enhanced drug delivery in adult patients with diffuse gliomas. Methods: A systematic search of PubMed/MEDLINE and Scopus was performed using pre-specified search terms (last search: June 2026). Eligible studies included clinical trials and cohort studies enrolling adult patients (≥18 years) with histologically confirmed diffuse glioma (WHO grades II–IV) who underwent FUS-BBBO for therapeutic drug delivery enhancement. Two reviewers independently screened records and extracted data using a standardized form. Study quality was assessed using the NIH Quality Assessment Tool for Before-After Studies (single-arm studies) and the ROBINS-I tool (comparative studies). The review was retrospectively registered on OSF. Results were synthesized narratively due to study heterogeneity. Results: Eight publications from seven independent clinical studies were included. Across these publications, 68 patient entries were reported; however, because of overlapping populations across publications, the number of unique patients could not be precisely determined. Two FUS platforms were employed, with the ExAblate Neuro system (220–230 kHz) used in six out of seven cohorts. BBB opening was confirmed in all studies, with target sonication success rates of 92.4–100%. No procedure-related serious adverse events attributable to FUS-BBBO were reported across any study. Transient T2/SWAN hypointense foci were observed in a subset of patients, consistently asymptomatic and histologically benign. Direct intratumoral drug quantification was feasible in two pre-surgical studies, demonstrating a 2.2-fold increase in drug accumulation in FUS-treated versus untreated tissue (p < 0.01). The only comparative study reported a statistically significant improvement in overall survival (median 31.3 vs. 19.3 months; HR 0.50, p = 0.009) and progression-free survival (median 13.5 vs. 8.1 months; HR 0.55, p = 0.020) versus the controls. Conclusions: FUS-mediated BBBO is a safe and feasible approach for enhancing drug delivery in adult diffuse glioma patients across multiple platforms and drug combinations. Preliminary comparative data suggest a potential survival benefit in newly diagnosed GBM; however, these findings are based on a single non-randomized study and require confirmation in prospective randomized controlled trials.