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Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance the stability, distribution, cellular uptake, and safety of nucleic acids. Previously, we engineered heavily and fully modified SpyCas9 crRNA and tracrRNA, which showed enhanced stability and retained activity when delivered to cultured cells in the form of the ribonucleoprotein complex. In this study, we report that a short, fully stabilized oligonucleotide (a \u2018protecting oligo\u2019), which can be displaced by tracrRNA annealing, can significantly enhance the potency and stability of a heavily modified crRNA. Furthermore, protecting oligos allow various bioconjugates to be appended, thereby improving cellular uptake and biodistribution of crRNA in vivo. Finally, we achieved in vivo genome editing in adult mouse liver and central nervous system via co-delivery of unformulated, chemically modified crRNAs with protecting oligos and AAV vectors that express tracrRNA and either SpyCas9 or a base editor derivative. Our proof-of-concept establishment of AAV\/crRNA co-delivery offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation.<\/jats:p>","DOI":"10.1093\/nar\/gkad1125","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T17:31:22Z","timestamp":1699896682000},"page":"977-997","source":"Crossref","is-referenced-by-count":18,"title":["Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing\n                    <i>in vivo<\/i>"],"prefix":"10.1093","volume":"52","author":[{"given":"Han","family":"Zhang","sequence":"first","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester , MA\u00a0 01605 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Kelly","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester , 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