Genome editing holds great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR/Cas to solid tumours for efficient cancer therapy remains challenging. Here we targeted tumour tissue mechanics via a multiplexed dendrimer lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA and sgRNA (siFAK + CRISPR-LNPs) to enable tumour delivery and enhance gene-editing efficacy. We show that gene editing was enhanced >10-fold in tumour spheroids due to increased cellular uptake and tumour penetration of nanoparticles mediated by FAK-knockdown. siFAK + CRISPR-PD-L1-LNPs reduced extracellular matrix stiffness and efficiently disrupted PD-L1 expression by CRISPR/Cas gene editing, which significantly inhibited tumour growth and metastasis in four mouse models of cancer. Overall, we provide evidence that modulating the stiffness of tumour tissue can enhance gene editing in tumours, which offers a new strategy for synergistic LNPs and other nanoparticle systems to treat cancer using gene editing.
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D.J.S. acknowledges support from the Cancer Prevention and Research Institute of Texas (CPRIT) (RP190251), the National Institutes of Health (NIH) (R01 EB025192-01A1, R01 CA269787-01), the American Cancer Society (ACS) (RSG-17-012-01) and the Cystic Fibrosis Foundation (CFF) (SIEGWA18XX0). H.Z. acknowledges support from the NIH (R01 DK111588, R01 DK125396, R01 CA251928), the Moody Medical Research Institute and an Emerging Leader Award from the Mark Foundation for Cancer Research (#21-003-ELA). We also acknowledge the UTSW Tissue Resource (National Cancer Institute (5P30CA142543)) and the Moody Foundation Flow Cytometry Facility. T.W. acknowledges a CPRIT Training Grant (RP160157). L.T.J. acknowledges the Pharma Foundation. We are also very grateful to Z. S. Guo (University of Pittsburgh) for sharing ID8-Luc cells with us.
D.J.S. is a co-founder and consultant of ReCode Therapeutics, which has licensed intellectual property from UT Southwestern. H.Z. has a sponsored research agreement with Alnylam Pharmaceuticals, consults for Flagship Pioneering and serves on the Scientific Advisory Board of Ubiquitix. H.Z.’s interests are not directly related to the contents of this paper. The other authors declare no competing interests.
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Zhang, D., Wang, G., Yu, X. et al. Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Nat. Nanotechnol. 17, 777–787 (2022). https://doi.org/10.1038/s41565-022-01122-3