Difficulties in the highly sensitive detection of tumour microfoci represent a critical obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons' subjective experience are limited by their inability to effectively detect tumour lesions measuring less than 2 mm; however, intraoperative fluorescence molecular imaging may overcome this limitation. Here, we synthesised an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumour-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumour specificity enabled the identification of residual microtumours and satellite lesions measuring less than 1 mm in living mice. Histological analysis validated the sensitivity and accuracy of this approach. We believe this technique utilising a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.