To directly compare the surface modifier effects on the property regulation of nanoparticle (NP)-based systems, a fluorescence quenched nanoprobe (GpF) responsive to matrix metalloproteinases (MMPs) is employed as a demonstration. Polyethylene glycol (PEG) and bovine serum albumin (BSA) are modified on the surface of GpF via different modes, the SAu covalent bond and nonspecific interaction, respectively. PEG and BSA display similarly protective capability to GpF and increase their biocompatibility that are demonstrated in stability, cytotoxicity, and hemolysis studies. Although PEGylated NPs show better in vivo long circulation property than BSA-decorated ones, the merit of BSA in controlling the system size in a relatively small range improves the penetration of GpF-BSA in tumor tissues and reduces the accumulation in normal tissues. Through an MMP-dominated catalysis and then a glutathione-assisted replacement process, the fluorescence recovery of GpF-BSA shows higher efficiency than PEG-modified NPs. It can be explained by the low steric hindrance and exchangeable manner of BSA on the surface of GpF. The results in this work demonstrate that an endogenous protein having dysopsonization function will be a promising material for the construction and surface modification of nanosystems for biomedical applications.