Ultrasound-responsive nanotheranostic systems for glioblastoma: Materials evolution, design strategies and clinical translation perspectives

Abstract

Glioblastoma (GBM) remains one of the most aggressive primary brain malignancies, characterized by a poor prognosis and limited therapeutic efficacy due to the restrictive nature of the blood–brain barrier (BBB), marked tumour heterogeneity, and the rapid development of therapeutic resistance. These challenges significantly hinder the effective delivery of therapeutic agents and necessitate the development of innovative treatment strategies capable of improving both drug targeting and treatment outcomes. This review comprehensively examines the evolution of ultrasound-responsive nanotheranostic systems for GBM, with particular emphasis on material design, mechanistic principles, and translational potential. We discuss the molecular and biological characteristics of GBM, including isocitrate dehydrogenase (IDH) mutation status, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and dysregulated signalling pathways, which inform the rational design of nanocarriers. In addition, the fundamental mechanisms of ultrasound, including cavitation, acoustic streaming, and hyperthermia, are highlighted for their roles in enhancing BBB permeability and enabling site-specific drug release. Furthermore, the review critically evaluates various classes of ultrasound-responsive nanocarriers, including microbubbles, nanodroplets, liposomes, and hybrid inorganic–organic nanoparticles, with respect to their physicochemical characteristics, imaging capabilities, and therapeutic performance. The progression from first-generation organic systems to advanced multifunctional nanoplatforms incorporating targeting ligands, gene-editing technologies, immunomodulators, and artificial intelligence (AI) assisted optimization is comprehensively discussed. Current challenges related to clinical translation, including safety, manufacturing scalability, regulatory considerations, and cost-effectiveness, are also examined. Overall, ultrasound-responsive nanotheranostic systems represent a promising strategy for precision glioblastoma therapy by integrating targeted drug delivery with real-time imaging and externally controlled therapeutic activation. Continued advances in focused ultrasound, multifunctional nanomaterials, artificial intelligence, and precision medicine may help to accelerate the clinical translation of these technologies and potentially improve therapeutic efficacy and survival outcomes for patients with glioblastoma.