Biodegradable Acoustic Targeting for Ultrasound-Supported Gene Therapy (BATUS) in Glioblastoma

Glioblastoma (GBM) remains one of the most challenging brain malignancies due to the restrictive nature of the blood-brain barrier (BBB), which severely limits effective drug and gene delivery. To overcome this, we introduce Biodegradable Acoustic Targeting for Ultrasound-Supported Gene Therapy (BATUS), a modular platform that enables safe, repeated, and targeted gene delivery to the brain. BATUS integrates an implantable, fully biodegradable glycine-based ultrasound (US) transducer, surgically placed via craniotomy for precise BBB opening, along with customizable peptide-targeted liposomal gene carriers. This system combines US-mediated transient BBB disruption with ligand-directed cellular targeting to enable efficient delivery across both vascular and cellular barriers. As a proof-of-concept, BATUS was evaluated using tLyp1-functionalized liposomes carrying PD-L1-targeting siRNA for GBM immunotherapy: in vitro evaluations confirmed efficient siRNA entrapment, stability, and specific cellular uptake, while in vivo studies in orthotopic GL261 GBM mouse models showed enhanced BBB permeability, significant PD-L1 silencing, reduced tumor growth, and prolonged survival. Crucially, BATUS exhibited a favorable safety profile, with no detectable local or systemic toxicity in animal models. By providing a modular framework where targeting ligands and genetic cargo are easily adaptable, BATUS is established as a strategy for precision gene delivery across the BBB, as demonstrated here for GBM.