Enhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. However, the median tumor targeting of current nanocarriers is only 0.7% injection dose, which demands more thorough understandings of other key factors in the drug delivery. Herein, we conducted head-to-head comparison between 5nm renal-clearable and 30nm non-renal-clearable gold nanoparticle (AuNP)-based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While these two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy and therapeutic index were enhanced 2, 7 and 10 times by 5-nm DDS over 30-nm one, respectively. These findings indicate that high vascular permeability of renal-clearable nanocarriers can be utilized to further improve anticancer drug delivery with no need of prolonged blood retention.