The tumor microenvironment-sensitive prodrug-based nanoparticles (NPs) have emerged as a promising drug delivery system (DDS). The shape of these particles plays a crucial role in their in vivo behavior. However, non-spherical organic NPs are rarely reported due to the inherent flexibility and variability of organic molecules. Herein, we fabricate reduction-sensitive prodrug NPs and explore the impact of their morphology properties on their in vivo fate. Prodrugs are self-assembled into spherical NPs with distearoyl phosphoethanolamine-PEG2000 (DSPE-PEG_2K), or into rod-shaped NPs with D-α-tocopherol polyethylene glycol 2000 succinate (TPGS_2K) due to the stronger binding energy. In comparison with spherical NPs, the endocytosis of rod-shaped NPs predominantly relies on caveolae-mediated pathways rather than clathrin-mediated ones, potentially avoiding degradation by lysosomes. Additionally, the rod-shaped NPs exhibit prolonged circulation time, increased tumor accumulation, and enhanced antitumor ability. Our current findings reveal the significant effect of particle shape on the behavior of prodrug NPs and introduce a novel paradigm for high-efficacy cancer therapy of prodrug NPs.