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Advances in mRNA technologies and lipid nanoparticle (LNP) delivery systems led to several clinical trials involving LNP\u2010CRISPR\u2010Cas9 mRNA\u2010based therapeutics. Despite these advances, achieving cell\u2010type\u2010specific extrahepatic mRNA delivery is still challenging. This study introduces a safe and effective intratumoral EGFR\u2010targeted CRISPR\u2010LNP delivery strategy for knocking out SOX2, which is a cancer\u2010specific gene. To assess their therapeutic potential, it is shown that LNPs made from ionizable lipids with helper lipids co\u2010encapsulating Cas9 mRNA and sgRNA targeting SOX2 (sgSOX2), lead to a \u224860% reduction in HNSCC cell viability in vitro. Next, using a xenograft HNSCC mouse model, targeted delivery of \ud835\udf36EGFR\u2010 CRISPR\u2010sgSOX2\u2010LNPs to HNSCC cells resulted in a 90% inhibition of tumor growth and a 90% increase in survival for &gt;\u00a084 days, with tumor disappearance observed in 50% of the mice. 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