A CRISPR-Cas13a-based system for spatial-controlled genome editing and cancer therapy is reported in Science Advances this week. CRISPR-Cas13a has emerged as a powerful system for RNA silencing, capable of cleaving both targeted RNA and nearby non-targeted RNA. This so-called collateral effect suggests that it may be effective in cancer treatment, enabling resistance to tumors' escape mechanisms, but the excessive and constantly active Cas13a also raises safety concerns. Thus, using CRISPR/Cas13a therapeutically requires controlling the RNase activity of Cas13a across spatial dimensions. To that end, Chongqing Medical University scientists developed hierarchical self-uncloaking CRISPR-Cas13a–customized RNA nanococoons — dubbed RNCOs-D — which feature tumor-specific recognition and spatial-controlled activation of Cas13a. RNCOs-D consists of programmable RNA nanosponges capable of targeted delivery and caging of chemotherapeutic drugs, along with nanocapsules anchored on the nanosponges for cloaking Cas13a/CRISPR RNA ribonucleoprotein activity. The tumor intracellular acidic microenvironment induces self-uncloaking of nanocapsules to allow spatial-controlled gene silencing by the intact CRISPR-Cas13a system and drug release via Cas13a transcleavage after cis-recognition of the mRNA target. The researchers demonstrate their approach by silencing mRNA for the tumor-specific mutation EGFR variant III in glioblastoma cells in vitro and in vivo.
Science Paper on Spatial-Controlled Genome Editing
May 20, 2022