Hepatocellular carcinoma targeted and pH-sensitive Ag2S loaded poly(lactic-co-glycolic acid (PLGA) nanoparticles (SP94—PLGA@Ag2S) were prepared by coprecipitation and chemical band combination method for near-infrared region Ⅱ fluorescence-guided surgical resection of hepatocellular carcinoma. The in vitro and in vivo experimental results showed that the nanoparticles tend leads to produce degradation under acidic conditions（pH6.5）, leading to the increase of the distance between Ag2S nanoparticles and the recovery of fluorescence（from 20% to 100%）. The degradation of the nanoparticles could realize the accurate differentiation between hepatocellular carcinoma tissues and normal tissues. In addition, the injection of nanoparticles with the assistance of near-infrared region (NIR) Ⅱ fluorescent surgical navigation equipment can effectively remove hepatocellular carcinoma, greatly prolong the lifetime （compared with the traditional surgery, the survival rate at 60 days after surgery increased from 40% to 90%） and postoperative life quality of tumor-bearing mice, and effectively reduce the postoperative recurrence rate.