Stimuli-responsive nanomedicine shows high therapeutic effects and low side effects to tumor cells and tissues, representing a preferable therapeutics for cancer therapy. Herein, we design an acid-stimuli-responsive doxorubicin polymeric prodrug (OM@DOX), and this amphiphilic prodrug has a unique chemical structure with prominent advantages, including high drug loading rate (as high as 61.5 wt%), pH-triggered drug release and targeted access to cells. This smart polymeric prodrug has a preferable size of similar to 40 nm and strong micellar stability in aqueous solution, which is benefited to the long blood circulation and efficient extravasation from tumor vessel. Moreover, the prodrug micelles showed a higher cytotoxicity against tumor cells (HeLa cells) than normal cells (L929 cells), likely suggesting the potential tumor-specific targeting ability. To render this prodrug micelles with targeting function, folic acid (FA) molecules conjugated prodrug (FA-OM@DOX) further showed selectively higher cytotoxicity to KB tumor cells (FA-receptor-positive) than A549 tumor cells (FA-receptor-negative). Considering the rapidly cell-penetrating ability and aforementioned features, we believe that the present prodrug strategy has the potential as a promising nanomedicine and providing inspired insights to design multifunctional drug delivery nanoplatforms.