Supramolecular Genome Editing: Targeted Delivery and Endogenous Activation of CRISPR/Cas9 by Dynamic Host‐Guest Recognition

作者：Bowen Li, Qing Li, Zidan Qi, Zhiyao Li, Xiaojie Yan, Yuan Chen, Xiaojie Xu, Qi Pan, Yuxuan Chen, Feihe Huang, Ping Yuan · 发表于：Angewandte Chemie International Edition · 年份：2024 · DOI：10.1002/anie.202316323 · 被引用次数：19 · 研究领域：CRISPR and Genetic Engineering、Advanced biosensing and bioanalysis techniques、RNA Interference and Gene Delivery

We synthesize supramolecular poly(disulfide) (CPS) containing covalently attached cucurbit[7]uril (CB[7]), which is exploited not only as a carrier to deliver plasmid DNA encoding destabilized Cas9 (dsCas9), but also as a host to include trimethoprim (TMP) by CB[7] moieties through the supramolecular complexation to form TMP@CPS/dsCas9. Once the plasmid is transfected into tumor cells by CPS, the presence of polyamines can competitively trigger the decomplexation of TMP@CPS, thereby displacing and releasing TMP from CB[7] to stabilize dsCas9 that can target and edit the genomic locus of PLK1 to inhibit the growth of tumor cells. Following the systemic administration of TMP@CPS/dsCas9 decorated with hyaluronic acid (HA), tumor-specific editing of PLK1 is detected due to the elevated polyamines in tumor microenvironment, greatly minimizing off-target editing in healthy tissues and non-targeted organs. As the metabolism of polyamines is dysregulated in a wide range of disorders, this study offers a supramolecular approach to precisely control CRISPR/Cas9 functions under particular pathological contexts.