Nanoparticle-Based Combinational Strategies for Overcoming the Blood-Brain Barrier and Blood-Tumor Barrier


Su Hyun Lim, Gi Taek Yee*, Dongwoo Khang*

The blood-brain barrier (BBB) and blood-tumor barrier (BTB) pose substantial challenges to efficacious drug delivery for

glioblastoma multiforme (GBM), a primary brain tumor with poor prognosis. Nanoparticle-based combinational strategies have

emerged as promising modalities to overcome these barriers and enhance drug penetration into the brain parenchyma. This review

discusses various nanoparticle-based combinatorial approaches that combine nanoparticles with cell-based drug delivery, viral drug

delivery, focused ultrasound, magnetic field, and intranasal drug delivery to enhance drug permeability across the BBB and BTB. Cellbased

drug delivery involves using engineered cells as carriers for nanoparticles, taking advantage of their intrinsic migratory and

homing capabilities to facilitate the transport of therapeutic payloads across BBB and BTB. Viral drug delivery uses engineered viral

vectors to deliver therapeutic genes or payloads to specific cells within the GBM microenvironment. Focused ultrasound, coupled with

microbubbles or nanoparticles, can temporarily disrupt the BBB to increase drug permeability. Magnetic field-guided drug delivery

exploits magnetic nanoparticles to facilitate targeted drug delivery under an external magnetic field. Intranasal drug delivery offers

a minimally invasive avenue to bypass the BBB and deliver therapeutic agents directly to the brain via olfactory and trigeminal

pathways. By combining these strategies, synergistic effects can enhance drug delivery efficiency, improve therapeutic efficacy, and

reduce off-target effects. Future research should focus on optimizing nanoparticle design, exploring new combination strategies, and

advancing preclinical and clinical investigations to promote the translation of nanoparticle-based combination therapies for GBM.