Herein, for accurate tumor‐targeting delivery and efficient gene editing, we exploited the SP94 polypeptide, hepatocellular cancer cell‐specific binding peptide,[25] and disulfide‐cross‐linking (SS)‐modified TME‐responsive nanocapsules (SNCSS) that encapsulate the Cas9 ribonucleoprotein/sgRNA complex for specific and noninvasive GDF15 gene knockout at the tumor site, thereby overcoming the current challenges of in vivo CRISPR/Cas9 gene editing therapy. This evidence concerns the gene GDF15 and hepatocellular carcinoma.