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Although development of nanomedicines has been a promising direction in tumor treatment, the therapeutic outcome of current nanomedicines is unsatisfying, partly because of the poor retention and penetration in tumors. Recently, a kind of tumor microenvironment sensitive size shrinkable nanoparticles (DOX-AuNPs-GNPs) has been developed by our lab, which could enhance the tumor penetration and retention depending on the size shrinking. However, the further enhancement is still restricted by dense collagen network in tumors. Thus in this study, we combined DOX-AuNPs-GNPs with losartan to deplete tumor collagen (constituted up to 90% of extracellular matrix) to further improve tumor penetration. In vitro, DOX-AuNPs-GNPs can shrink from over 117.8 nm to less than 50.0 nm and release DOX-AuNPs under the triggering of tumor overexpressed matrix metalloproteinases-2 (MMP-2). In vivo, pretreatment …