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We herein developed a tumor cell\u2010selective CRISPR\/Cas9 gene editing system by introducing a complementary single\u2010stranded DNA (ssDNA) containing apurinic\/apyrimidinic (AP) sites (AP\u2010ssDNA) along the target region of single\u2010guided RNA (sgRNA). The engineered hybrid (AP\u2010ssDNA\/sgRNA) could tracelessly release the native sgRNA in tumor cells due to cleavage of AP\u2010ssDNA by the overexpressed apurinic\/apyrimidinic endonuclease 1 (APE1), thus enabling tumor\u2010selective gene editing. Subsequently, a biodegradable lipid nanoparticle based on dynamic covalent bonding was developed to codeliver Cas9\u2010encoding mRNA (mCas9) with AP\u2010ssDNA\/sgRNA targeting the SUV39H1 gene, which mediated silence of cyclic GMP\u2010AMP synthase (cGAS) methylation to activate stimulator of interferon genes (STING) and enhanced antitumor immunity. As thus, when coupled with radiotherapy, the gene editing platform provoked robust antitumor efficacy in B16F10 xenograft tumor\u2010bearing mice. This study provides a versatile paradigm for conditionally controlled gene editing and highlights the therapeutic potential of cGAS demethylation in reactivating cGAS\u2010STING pathway for antitumor immunotherapy.<\/jats:p>","DOI":"10.1002\/anie.6610006","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T09:03:01Z","timestamp":1791882181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hybridization\u2010Mediated Reversible sgRNA Caging Enables Tumor\u2010Selective Gene Editing for Potentiating Antitumor Immunity via cGAS Demethylation"],"prefix":"10.1002","author":[{"given":"Haoyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Functional Nano and Soft Materials (FUNSOM) Jiangsu Key Laboratory of Advanced Healthcare Materials and Devices Soochow University  Suzhou 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