1 Scientific RepoRts | 6:38541 | DOI: 10.1038/srep38541 www.nature.com/scientificreports Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells Akhil srivastava 1,2,* , Narsireddy Amreddy 1,2,* , Anish Babu 1,2 , Janani panneerselvam 1,2 , Meghna Mehta 3,2 , Ranganayaki Muralidharan 1,2 , Allshine Chen 4 , Yan Daniel Zhao 4,2 , Mohammad Razaq 5,2 , Natascha Riedinger 6 , Hogyoung Kim 7 , shaorong Liu 8,2 , si Wu 8,2 , Asim B. Abdel-Mageed 7 , Anupama Munshi 3,2 & Rajagopal Ramesh 1,2,9 Successful chemotherapeutic intervention for management of lung cancer requires an efcient drug delivery system. Gold nanoparticles (GNps) can incorporate various therapeutics; however, GNps have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (exo) can ferry GNp- therapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel exo-GNp-based therapeutic delivery system -‘nanosomes’- for lung cancer therapy. this system consists of GNps conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (exo-GNp-Dox). the therapeutic efcacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fbroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). the enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved Ros-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efcient delivery of therapeutics to cancer cells. Extensive research in the area of cancer therapeutics has resulted in the discovery and synthesis of many potent small molecule inhibitors with excellent anti-cancer activity 1,2 . Despite such tremendous progress, many of these therapeutic molecules have remained at the investigational level, and could not be used for clinical interventions 3 . Conventional therapeutic molecules, such as synthetic drugs, compounds extracted from natural resources, or bio- molecules like inhibitory RNA/DNA, do not bear any targeting signals specifc to proliferating tumor cells, and produce of-target cytotoxicity 4 . In addition, many of molecules of therapeutic importance are hydrophobic and/or negatively charged, which results in their poor bioavailability to cancer cells 5,6 . To circumvent these drawbacks, recent advances in nanotechnology have resulted in the development of various drug delivery vehicles, such as liposomes, polymer-based and inorganic nanoparticles that can be conjugated to signaling molecules and used for targeted tumor therapy 7–10 . Current delivery systems for anticancer therapeutics are plagued by numerous disadvantages related to low efciency, poor bio-distribution, and immune response, limiting their application in clinical settings 11 . Exosomes are submicron-sized cellular vesicles released by cells and can be isolated from all bodily fuids and from the medium of growing cells 12 . Recently, it has been recognized that exosomes can ferry biomolecules, such 1 Department of Pathology, University of Oklahoma Health Sciences center, Oklahoma city, OK, USA. 2 Stephenson cancer center, University of Oklahoma Health Sciences center, Oklahoma city, OK, USA. 3 Department of Radiation Oncology, University of Oklahoma Health Sciences center, Oklahoma city, OK, USA. 4 Department of epidemiology and Statistics, University of Oklahoma Health Sciences center, Oklahoma city, OK, USA. 5 Department of Medicine, University of Oklahoma Health Sciences center, Oklahoma city, OK, USA. 6 Boone Pickens School of Geology, Oklahoma State University, Stillwater, OK, USA. 7 Department of Urology, tulane University School of Medicine, new Orleans, LA, USA. 8 Department of chemistry and Biology, University of Oklahoma, norman, OK, USA. 9 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences center, Oklahoma city, OK, USA. * these authors contributed equally to this work. correspondence and requests for materials should be addressed to R.R. (email: rajagopal-ramesh@ouhsc.edu) Received: 25 October 2016 Accepted: 03 November 2016 Published: 12 December 2016 opeN