Most hepatocellular carcinomas (HCCs) occur in cirrhotic livers, but unequivocal diagnosis of early HCC from the fibrotic microenvironment remains a formidable challenge with conventional imaging strate- gies, mainly because of the massive fibrotic collagen deposition leading to hepatic nodules formation and dysfunction of contrast agent metabolism. Here, we developed a “sweep-and-illuminate”imaging strat- egy, pre-degrade hepatic fibrotic collagen with collagenase I conjugated human serum albumin (HSA- C) and then targeting visualize HCC lesion with GPC3 targeting nanoparticles (TSI NPs, TJ2 peptide–superparamagnetic iron oxide–indocyanine green) via fluorescence imaging (FLI) and magnetic parti- cle imaging (MPI). TSI NPs delineated a clear boundary of HCC and normal liver, and the tumor-to- background ratios (TBRs) detected by FLI and MPI were 5.43- and 1.34-fold higher than the non-targeted group, respectively. HSA-C could degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspe- cific NPs retention in mice with liver fibrosis. In a pathological state in which HCC occurs in the fibrotic microenvironment, HSA-C-mediated pre-degradation of fibrotic collagen reduced background signal in- terference in fibrotic tissues and enhanced the intratumoral uptake of TSI NPs, resulting in the clear demarcation between HCC and liver fibrosis, and the TBR was increased 2.61-fold compared to the group without HSA-C pretreatment. We demonstrated the feasibility of combined pre-degradation of fibrotic collagen and application of a GPC3-targeted FLI/MPI contrast agent for early HCC identification, as well as its clinical value in the management of patients with advanced liver fibrosis.