RBC-derived vesicles as a systemic delivery system of doxorubicin for lysosomal-mitochondrial axis-improved cancer therapy
Shuhui Wu, Chia-Chu Hsieh, Szu-Chun Hsu, Ming Yao, Jong‐Kai Hsiao, Shih‐Wei Wang, Chih‐Peng Lin, Dongming Huang
Abstract
Introduction: 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: antitumor mechanism and efficacy in a panel of cancer cell lines. Results: . 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.