Wu S.-H.Hsieh C.-C.SZU-CHUN HSUMING YAOHsiao J.-K.Wang S.-W.CHIH-PENG LINHuang D.-M.2021-01-052021-01-0520212090-1232https://www.scopus.com/inward/record.uri?eid=2-s2.0-85097402456&doi=10.1016%2fj.jare.2020.11.009&partnerID=40&md5=d49a2344ee4bc0bfa5373ec76c9d423dhttps://scholars.lib.ntu.edu.tw/handle/123456789/537904Introduction: Chemotherapeutic drugs are the main intervention for cancer management, but many drawbacks impede their clinical applications. Nanoparticles as drug delivery systems (DDSs) offer much promise to solve these limitations. Objectives: A novel nanocarrier composed of red blood cell (RBC)-derived vesicles (RDVs) surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs was investigated for improved cancer therapy. Methods: We investigated the in vivo antineoplastic performance of Dox-gluRDVs through intravenous (i.v.) administration in the mouse model bearing subcutaneous (s.c.) B16F10 tumor and examined the in vitro antitumor mechanism and efficacy in a panel of cancer cell lines. Results: Dox-gluRDVs can exert superior anticancer activity than free Dox in vitro and in vivo. Distinct from free Dox that is mainly located in the nucleus, but instead Dox-gluRDVs release and efficiently deliver the majority of their conjugated Dox into lysosomes. In vitro mechanism study reveals the critical role of lysosomal Dox accumulation-mediated mitochondrial ROS overproduction followed by the mitochondrial membrane potential loss and the activation of apoptotic signaling for superior anticancer activity of Dox-gluRDVs. Conclusion: This work demonstrates the great potential of RDVs to serve a biological DDS of Dox for systemic administration to improve conventional cancer chemotherapeutics. ? 2020[SDGs]SDG3journal article10.1016/j.jare.2020.11.0092-s2.0-85097402456