Molecular therapy : the journal of the American Society of Gene TherapySep 29, 2025

Using tiny particle delivery to turn off androgen receptors in treatment-resistant prostate cancer cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

Extracellular vesicles successfully delivered the Cas9/single-guide RNA complex, leading to gene editing in prostate cancer cells.

Gene editing was achieved by silencing the androgen receptor (AR) gene at the genomic DNA level.
N-myristoylation of the Cas9 protein improved the encapsulation of the editing complex into extracellular vesicles.
Gene editing efficiency varied among prostate cancer cell lines, linked to differences in chromatin accessibility.
The Cas9/single-guide RNA complex did not change AR mRNA levels but significantly reduced the expression of AR downstream genes.
EV-mediated delivery effectively introduced indels into the AR gene and inhibited proliferation in enzalutamide-resistant prostate cancer cells.

Simplified

CRISPR-mediated gene editing is a promising technology for treatment of diseases by silencing a driver gene at the genomic DNA level. However, delivery of CRISPR machinery remains challenging for potential therapeutic application. Here, we developed a platform using extracellular vesicles (EVs) as a vehicle to deliver Cas9/single-guide RNA (sgRNA) ribonucleoprotein (RNP) complex to silence androgen receptor (AR) gene in prostate cancer (PCa) cells. A genetic modification conferred the N-myristoylation to the Cas9 protein, which enhanced the encapsulation of Cas9/sgRNA RNP into EVs and silenced both ectopic and endogenous AR gene. Interestingly, gene editing efficiency varied across PCa cell lines, associated with different chromatin accessibility at the target site. Functional analyses demonstrated that Cas9/sgRNA RNP (targeting the N-terminal domain of the AR gene) did not change gene-edited AR mRNA levels, but significantly inhibited expression levels of AR downstream genes, thereby attenuating PCa cell proliferation. Importantly, EV-mediated delivery of the Cas9/sgRNA RNP introduced indels into the AR gene and inhibited proliferation of enzalutamide-resistant PCa cells. This study highlights a therapeutic strategy for treatment of castration-resistant PCa using a programmable EV-mediated delivery platform.

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Competing interests

Declaration of interests H.C. holds a patent, PCT/US2020/026321, titled “delivery of CRISPR/MCAS9 through exosomes for genome editing.”

PubMed

Using tiny particle delivery to turn off androgen receptors in treatment-resistant prostate cancer cells

Abstract

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Competing interests

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Abstract

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Related papers

You found one interesting study. We’ll send the next 7.

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