Objective To prepare hyaluronic acid(HA)-based reactive oxygen species(ROS)responsive podophyllotoxin(POD)polymeric prodrug micelle HTP-M,and to investigate its inhibitory activity on oral squamous cell carcinoma(OSCC)SCC-9 cells.Methods The HA-based ROS-responsive POD polymeric prodrug HA-TK-POD was synthesized by a two-step esterification method.The polymer prodrug micelle HTP-M was prepared by dialysis method,and its morphological characteristics,particle size,Zeta potential,and drug loading efficiency were measured.Meanwhile,the ROS-responsive drug release was also investigated.The in vitro and in vivo antitumor efficiency of HTP-M micelles was evaluated using SCC-9 cells and SCC-9-tumor-bearing mice as the models.Results The successful synthesis of HA-TK-POD polymer prodrug was confirmed by 1 H-NMR.The obtained HTP-M micelles have a spherical morphology and uniform distribution,and their particle size and zeta potential were(126.1±3.5)nm and(-26.8±1.9)mV,respectively.Moreover,the HTP-M micelles have a high drug loading efficiency(12.3±0.8)%with good ROS responses.HTP-M can specifically target to CD44 overexpression cancer cells,and showed good anticancer effect in vitro and in vivo.Conclusion A ROS-responsive POD polymer prodrug micelle HTP-M based on HA has been prepared in this paper,which has good ROS response and can effectively inhibit the proliferation of OSCC cells and tumor-bearing mice.This work provides a new strategy for the treatment of clinical OSCC.