Cell biomaterialsSep 16, 2026

Removing a Drug-Resistance Protein from Brain Tumors Using Focused Ultrasound and CRISPR Gene Editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 17, 2026

Abstract

Convection-enhanced delivery of a CRISPR Cas9 system to murine gliomas improved tumor response to paclitaxel.

The engineered CRISPR Cas9 ribonucleoprotein system targets specific regions of the gene encoding for P-glycoprotein.
Inhibition of P-glycoprotein's efflux function was observed in both tumor cells and endothelial cells.
Encapsulation of RNPs in lipid nanoparticles facilitates targeted delivery to gliomas using focused ultrasound.
Lipid nanoparticle delivery to gliomas not only inhibited efflux but also enhanced the efficacy of paclitaxel therapy.
The approach may allow for targeted treatment of brain tumors while minimizing effects on other organs.

Simplified

P-glycoprotein (P-gp), an efflux transporter expressed in endothelium and tumor cells, restricts drug delivery to gliomas. To address this, we engineered a CRISPR Cas9 ribonucleoprotein (RNP) system that targets indels to exons 4 and 10 of the gene encoding for P-gp. Convection-enhanced delivery of this duplexed RNP system to murine gliomas inhibited efflux function in tumor cells and endothelium and improved tumor response to paclitaxel, a P-gp substrate. We then encapsulated RNPs in a lipid nanoparticle (LNP) formulation that naturally traffics to the lungs, an organ devoid of P-gp expression, and delivered them to murine gliomas with focused ultrasound (FUS). FUS-targeted LNP-RNP delivery to gliomas inhibited efflux function in tumor cells and endothelium and enhanced paclitaxel therapy. Our results conceptually illustrate a strategy wherein LNP-encapsulated CRISPR Cas9 cargo in the bloodstream is targeted to the brain with FUS, while off-target LNPs are biochemically trafficked to an innocuous sink organ.

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Removing a Drug-Resistance Protein from Brain Tumors Using Focused Ultrasound and CRISPR Gene Editing

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