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Safia Naz,1,* Mingyu Wang,1,* Yuning Han,1 Bin Hu,1 Liping Teng,2 Juan Zhou,1 Huijie Zhang,1 Jinghua Chen11Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi, People’s Republic of China; 2Wuxi School of Medicine, Jiangnan University, Wuxi, People’s Republic of China*These authors contributed equally tothis workBackground: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties.Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH).Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells.Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.Keywords: mesoporous silica nanoparticles, drug delivery, enzyme-responsive, multistage-targeting, cancer therapy &nbsp