Focused ultrasound mediated gene therapy for glioblastoma: A preclinical in vivo systematic review and meta-analysis

Focused ultrasound (FUS) is a noninvasive modality for targeted delivery of therapeutic agents across the blood-brain barrier (BBB). We conducted a systematic review and meta-analysis to evaluate the efficacy of FUS-mediated gene therapy in preclinical orthotopic glioblastoma (GBM) in vivo models. PubMed, Embase, Scopus, and Web of Science were searched according with PRISMA guidelines to identify studies reporting FUS-mediated delivery of genetic material in orthotopic GBM animal models. Eligible studies assessed gene delivery or therapeutic efficacy in vivo . Data were extracted on vector type, gene payload, microbubble characteristics, and FUS parameters. Primary outcomes included tumor volume reduction, survival, and gene expression in brain tissue. Random-effects meta-analyses were performed to pool effect sizes. Nine studies met inclusion criteria, including viral, non-viral, nanoparticle, and exosome-based vectors. Delivered genes included therapeutic transgenes (MDA-7/IL-24, HSV-TK, shBirc5, CRISPR/Cas9) and reporter genes (luciferase, GFP). FUS parameters varied (0.65–1 MHz; 120–700 kPa; 1–3 min), as did microbubble formulations. Meta-analysis demonstrated FUS significantly enhanced gene expression in brain tissue (pooled effect size 6.34, 95% CI 2.21–18.18), tumor volume reduction (pooled effect size 4.03, 95% CI 1.46–11.12), and survival (HR 1.33, 95% CI 1.13–1.56). Heterogeneity was high, reflecting protocol variability. No significant FUS-related adverse effects were reported. FUS-mediated gene therapy improved gene delivery, tumor control, and survival in preclinical glioma models. These findings support FUS as a safe and effective strategy to overcome barriers to central nervous system gene therapy. Further studies are needed to standardize parameters and evaluate long-term outcomes before clinical translation. • FUS enables noninvasine BBB opening, enhancing intracranial gene therapy vector delivery in GBM. • FUS-mediated gene therapy improved expression, reduced tumor volume, and prolonged survival in vivo. • Viral, non-viral, and exosomal carriers all showed enhanced efficacy with FUS, indicating broad use. • No significant FUS-related adverse events were reported in animal models, supporting its safety. • Results supprt FUS as an adjunct CNS gene therapy platform and justify early-phase clinical trials.