Collectively, we develop a multifunctional nanoparticle formulation of afatinib and miR-139 with targeting, penetrating, and pH-responsive characteristics for simultaneous modulation of EGFR/HER/Ras/Akt/Rac1/STAT3/MAPK/EMT/Bcl-2 pathways to increase the sensitivity of colon cancer cells to afatinib. The gene discussed is BCL2; the disease is colonic neoplasm.