Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
Adv Sci (Weinh). 2024 Jun;11(21):e2308763. doi: 10.1002/advs.202308763. Epub 2024 Mar 29.
The CRISPR/Cas system has been introduced as an innovative tool for therapy, however achieving specific delivery to the target has been a major challenge. Here, an antibody-CRISPR/Cas conjugate platform that enables specific delivery and target gene editing in HER2-positive cancer is introduced. The CRISPR/Cas system by replacing specific residues of Cas9 with an unnatural amino acid is engineered, that can be complexed with a nanocarrier and bioorthogonally functionalized with a monoclonal antibody targeting HER2. The resultant antibody-conjugated CRISPR/Cas nanocomplexes can be specifically delivered and induce gene editing in HER2-positive cancer cells in vitro. It is demonstrated that the in vivo delivery of the antibody-CRISPR/Cas nanocomplexes can effectively disrupt the plk1 gene in HER2-positive ovarian cancer, resulting in substantial suppression of tumor growth. The current study presents a useful therapeutic platform for antibody-mediated delivery of CRISPR/Cas for the treatment of various cancers and genetic diseases.
CRISPR/Cas 系统已被引入作为一种治疗的创新工具，然而实现对靶标的特异性递送一直是一个主要挑战。在这里，引入了一种抗体-CRISPR/Cas 缀合物平台，该平台可实现 HER2 阳性癌症中的特异性递送和靶基因编辑。通过用非天然氨基酸替换 Cas9 的特定残基来工程化 CRISPR/Cas 系统，该系统可以与纳米载体复合，并通过针对 HER2 的单克隆抗体进行生物正交功能化。所得的抗体缀合的 CRISPR/Cas 纳米复合物可以在体外特异性递送至 HER2 阳性癌细胞，并诱导基因编辑。研究表明，抗体-CRISPR/Cas 纳米复合物的体内递送至 HER2 阳性卵巢癌中可以有效地破坏 plk1 基因，从而显著抑制肿瘤生长。本研究为抗体介导的 CRISPR/Cas 递送来治疗各种癌症和遗传疾病提供了一个有用的治疗平台。
