Bladder instillation of chemo-therapeutic agents is common for bladder cancer (BC) treatment, however, due to the poor tissue selectivity of chemotherapeutic agents, this method suffers from bladder irritation or even chemical cystitis. Here, we designed a hydroxyethyl starch-based prodrug for epirubicin (EPI) using a pH-sensitive hydrazone linker and folate as the active targeting moiety (FA-HES-hyd-EPI) to achieve delivery selectivity. Prodrug micelles decorated with FA (FA-m), with diameter of 203.6 ± 7.1 nm and EPI loading of 5.80 ± 0.129 %, were prepared by self-assemble method. FA-m was found with improved cellular uptake and stronger cytotoxicity over EPI. An orthotopic BC model was established with FA receptor over-expression, and FA-m showed significantly higher accumulation at tissue and cell levels compared with the FA-free counterpart. Besides, the systemic exposure of FA-m was significantly lower than EPI (AUC