Cationic liposomes induce cell necrosis through lysosomal dysfunction and late-stage autophagic flux inhibition.
The application of cationic liposomes (CLs) as nonviral vectors is hampered by their cellular toxicity. Thus we aim to investigate the mechanisms underlying the cellular toxicity of CLs.



The effect of CLs on the autophagic flux, autophagosome-lysosome fusion, lysosome membrane permeabilization and cell necrosis of liver cells was investigated.



Our results reveal a novel mechanism of CL-induced cell necrosis involving the induction of lysosome membrane permeabilization and late-stage autophagic flux inhibition that resulted in cytoplasmic release of cathepsin B, mitochondrial dysfunction and reactive oxygen species production, which are the key mediators of cell necrosis. Our study is important for revealing the cellular toxicity of CLs and designing safer gene delivery systems.
Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.|International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.|Department of Oncology, Affiliated Hospital of Guizhou Medcial University & Guizhou Cancer Hospital, Guiyang 550025, Guizhou, China.
Kaixuan
K
Yang
Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Ying
Y
Lu
Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.|Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
Fangyuan
F
Xie
Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Hao
H
Zou
International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.
Xiaoyu
X
Fan
International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.
Bohua
B
Li
International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.
Wei
W
Li
Department of Respiratory & Critical Care Medicine, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Wei
W
Zhang
Division of Life & Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
Lin
L
Mei
International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.|Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore.
Si-Shen
SS
Feng
Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
You
Y
Yin
Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
Yan
Y
Liu
Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
Hai
H
Zhang
Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Chuan
C
Yin
Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Yanqiang
Y
Zhong
Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.|International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.|Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
Jie
J
Gao
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002401:Cathepsin B / Q000378:metabolism; D002412:Cations; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000009:adverse effects; D065546:Drug Liberation; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000633:toxicity; D008247:Lysosomes / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009336:Necrosis / Q000139:chemically induced; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism
D002412:Cations; D008081:Liposomes; D017382:Reactive Oxygen Species; D002401:Cathepsin B
autophagic flux; cationic liposomes; cellular toxicity; gene therapy; lysosome membrane permeabilization; necrosis