{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T08:09:54Z","timestamp":1781165394177,"version":"3.54.1"},"posted":{"date-parts":[[2025,11,14]]},"group-title":"Genetics","reference-count":98,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health grant","doi-asserted-by":"crossref","award":["UG3TR004713"],"award-info":[{"award-number":["UG3TR004713"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health grant","doi-asserted-by":"crossref","award":["UG3\/UH3NS115597"],"award-info":[{"award-number":["UG3\/UH3NS115597"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009726","name":"Foundation for Angelman Syndrome Therapeutics","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009726","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Brain-wide genome-editing remains a major hurdle for the treatment of neurogenetic disorders. Here, we report a non-viral, non-nanoparticle, chemical modification-based method, called Stimuli-Responsive Traceless Engineering Platform (STEP) that achieves highly efficient and brain-wide genome-editing of neurons in mice. Using cholesterol-based STEP as a lead, we show that a single administration of STEP-ribonucleoproteins (RNPs) results in functional genetic rescue with significant improvements across a battery of neurobehavioral domains in the Angelman syndrome (AS) mouse model. No significant off-target events or general toxicity effects are observed. STEP-RNPs are also highly efficient at editing human neurons and cortical brain organoids differentiated from AS patient-derived iPSCs. scRNA-seq analysis confirms functional genetic rescue via reactivation of\n                  <jats:italic>Ube3a\/UBE3A<\/jats:italic>\n                  expression in human and mouse STEP-RNP-treated neuronal cells. Genome editing via STEP-RNPs has broad applications and the potential to treat many other neurogenetic disorders.\n                <\/jats:p>","DOI":"10.1101\/2025.11.13.684643","type":"posted-content","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T17:40:15Z","timestamp":1763142015000},"source":"Crossref","is-referenced-by-count":1,"title":["Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman 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