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Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy
Di Zhang1, Guoxun Wang2, Xueliang Yu1
1Department of Biochemistry, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature Nanotechnology
|May 13, 2022
Summary
Modifying tumor mechanics with lipid nanoparticles enhances CRISPR gene editing for cancer therapy. This approach improved nanoparticle delivery and inhibited tumor growth and metastasis in preclinical models.
Area of Science:
- Biotechnology
- Cancer Research
- Nanomedicine
Background:
- Genome editing, particularly CRISPR/Cas, shows promise for cancer treatment by targeting cancer-related genes.
- Efficient delivery of CRISPR/Cas systems to solid tumors remains a significant challenge for effective cancer therapy.
Purpose of the Study:
- To investigate the potential of targeting tumor tissue mechanics to enhance CRISPR/Cas gene editing efficacy for cancer treatment.
- To develop a multiplexed dendrimer lipid nanoparticle (LNP) system for co-delivery of focal adhesion kinase (FAK) siRNA and CRISPR/Cas components.
Main Methods:
- Co-delivery of FAK siRNA, Cas9 mRNA, and sgRNA using multiplexed dendrimer lipid nanoparticles (siFAK + CRISPR-LNPs).
- Assessment of nanoparticle delivery, cellular uptake, and tumor penetration in tumor spheroids.
- Evaluation of CRISPR/Cas-mediated gene editing, including disruption of PD-L1 expression.
- Testing the therapeutic efficacy of siFAK + CRISPR-PD-L1-LNPs in four preclinical cancer models.
Main Results:
- FAK knockdown via siRNA significantly enhanced nanoparticle cellular uptake and tumor penetration, leading to >10-fold increase in gene editing efficiency in tumor spheroids.
- siFAK + CRISPR-PD-L1-LNPs effectively reduced extracellular matrix stiffness and disrupted PD-L1 expression through CRISPR/Cas gene editing.
- Significant inhibition of tumor growth and metastasis was observed in multiple cancer models treated with the developed LNP system.
Conclusions:
- Modulating tumor tissue mechanics by targeting FAK is a viable strategy to enhance the delivery and efficacy of CRISPR/Cas gene editing systems in solid tumors.
- The developed multiplexed LNP system offers a novel approach for synergistic cancer therapy by combining mechanical modulation with gene editing.
- This strategy holds potential for improving nanoparticle-based cancer treatments utilizing gene editing technologies.
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