Low-intensity pulsed ultrasound-mediated nose-to-brain co-delivery of β-blockers and aPD-L1 enhances glioblastoma immunotherapy

Abstract Intranasal delivery offers a direct route to the brain, circumventing the blood-brain barrier (BBB) and minimizing systemic toxicity. However, its efficiency is mainly limited by the nasal mucosal barrier (NMB). Here, low-intensity pulsed ultrasound (LIPUS) without depending on the microbubbles (MBs) to amplify energy, is directly used to reversibly open the NMB by disrupting tight junction proteins. A bionic nanovesicle (iRGD-anti-programmed cell death ligand 1 (aPD-L1) & carvedilol (β-blocker) @ macrophage-derived extracellular vesicles, iMPC) is designed to co-deliver carvedilol for β-receptor blockade to reduce T-cell exhaustion, and aPD-L1 to enhance T-cell anti-tumor activity in orthotopic glioblastoma (GBM) mice during the two-hour window for NMB opening. Consequently, compared to free aPD-L1, up to a 33.38-fold increase of aPD-L1 in the GBM region is obtained with LIPUS-mediated intranasal delivery of iMPC. Reactivating T cells significantly enhances immunotherapy, leading to a 40% tumor reduction, extended survival, and long-term immune memory in orthotopic GBM mice. Overall, the LIPUS-mediated NMB opening strategy notably enhances nose-to-brain drug delivery efficiency, offering a promising platform for treating brain diseases.