A galactose‐decorated lipopolyplex (Gal‐SLP) is developed as a hepatocellular carcinoma (HCC)‐targeting self‐activated cascade‐responsive nanoplatform to co‐deliver sorafenib and USP22 shRNA (shUSP22) for synergetic HCC therapy. The gene discussed is USP22; the disease is hepatocellular carcinoma.