An Update on Blood-Brain Barrier Penetrating Nanoparticles for the Treatment of Glioblastoma

Abstract: Glioblastoma (GBM) is an aggressive and lethal primary brain malignancy, with patient survival largely unchanged over recent decades despite advances in surgery, radiotherapy and chemotherapy. A major therapeutic challenge is the blood–brain barrier (BBB), which restricts the delivery of many systemically administered drugs, including emerging biologic and gene-based therapies. Nanoparticle (NP) delivery systems have therefore attracted intense interest to overcome BBB-associated transport limitations, enhance tumor specificity and enable delivery of potent therapeutic cargos to infiltrative GBM cells. This review provides an overview of some recent advances in BBB-penetrating NP platforms for GBM treatment, spanning lipid-based, polymeric, dendrimer, inorganic, peptide-based and biomimetic systems. We discuss several extracellular and intracellular biological barriers to effective delivery, while outlining how these challenges may inform rational NP design. Targeting strategies exploiting a range of receptors are reviewed alongside stimuli-responsive systems and combination approaches that integrate BBB modulation techniques, including focused ultrasound and intranasal nose-to-brain delivery. While many NP platforms demonstrate compelling preclinical efficacy, translation to the clinic remains limited. We therefore discuss recent clinical developments and highlight select translational opportunities such as preclinical model selection, manufacturing scalability factors and regulatory considerations. As such there may be a need for integrated design strategies, clinically relevant model systems and robust biodistribution and toxicity assessment. Aligning advances in nanotechnology with GBM biology and clinical constraints may be essential in realizing the therapeutic promise of BBB-penetrating nanomedicines to improve outcomes for patients with this devastating disease. Collectively, BBB-penetrating NPs may represent a promising strategy for GBM treatment, and bridging the gap between preclinical success and clinical benefit may remain an opportunity for the field. Keywords: glioblastoma, blood-brain barrier, nanoparticle drug delivery, brain targeting, gene and RNA therapeutics, brain-targeted nanomedicine