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Nevertheless, it is imperative that the activity of the CRISPR\u2013dCas9 system be tightly controlled to improve its safety and applicability. In this study, we successfully designed a microRNA-activated CRISPR\u2013dCas9 system, termed miR-ON-CRISPR, in which the core components (dCas9 and sgRNA) are both regulated by endogenous miRNA. Our findings demonstrated that the miR-ON-CRISPR system can regulate firefly luciferase reporter gene expression to faithfully visualize miRNA activity and image the differentiation status of neural cells. Moreover, the miR-ON-CRISPR was designed as an AND\/OR gate system, thereby enabling the simultaneous detection of two distinct miRNAs. Furthermore, the system was adapted to achieve cell type-specific killing by activating the exogenous DTA genes or endogenous BAX genes. Finally, in mouse models of sepsis, the miR-ON-CRISPR system was shown to alleviate the sepsis-induced liver injury as well as the associated oxidative stress damage and endoplasmic reticulum\u00a0stress via activating the nuclear erythroid 2-related factor 2 gene. In conclusion, this proof-of-concept study demonstrates the feasibility of the miR-ON-CRISPR system for cell type-specific control of CRISPR\u2013dCas9 activity and its therapeutic applications in the treatment of genetic diseases.<\/jats:p>","DOI":"10.1093\/nar\/gkaf1037","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:17:12Z","timestamp":1758716232000},"source":"Crossref","is-referenced-by-count":8,"title":["MiR-ON-CRISPR: a microRNA-activated CRISPR\u2013dCas9 system for precise gene therapy in living cells and mouse models of sepsis"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5270-055X","authenticated-orcid":false,"given":"Wen-Jie","family":"Shu","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital of Xi\u2019an Jiaotong University Department of Medical Oncology, , Xi\u2019an , Shaanxi 710004 ,","place":["China"]},{"name":"Institute of Medical Engineering , Department of 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