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.

由于能够精确灭活或修复癌症相关基因，基因组编辑在癌症治疗方面具有巨大潜力。然而，将 CRISPR/Cas 递送至实体瘤以进行有效的癌症治疗仍然具有挑战性。在这里，我们通过多重树状聚合物脂质纳米颗粒 (LNP) 方法靶向肿瘤组织力学，该方法涉及粘着斑激酶 (FAK) siRNA、Cas9 mRNA 和 sgRNA (siFAK + CRISPR-LNP) 的共同递送，以实现肿瘤递送并增强基因编辑功效. 我们表明，由于 FAK 敲低介导的纳米颗粒的细胞摄取和肿瘤渗透增加，基因编辑在肿瘤球体中增强了 10 倍以上。siFAK + CRISPR-PD-L1-LNPs 通过 CRISPR/Cas 基因编辑降低细胞外基质硬度并有效破坏 PD-L1 表达，在四种癌症小鼠模型中显着抑制肿瘤生长和转移。总的来说，我们提供的证据表明调节肿瘤组织的硬度可以增强肿瘤中的基因编辑，这为协同 LNPs 和其他纳米颗粒系统提供了一种使用基因编辑治疗癌症的新策略。