Membrane Fusion Liposome-Mediated Ferroptosis Explosion for Enhanced Cancer Therapy

Kong，Fanhui1; Lei，Qi2; Ma，Yi1; He，Peiying1; Zheng，Guansheng1; Xu，Yue1; Huang，Junda1; Brinker，C. Jeffrey3; Liu，Kaisheng4; Zhu，Wei1

2023-06-27

10.1021/acs.chemmater.3c00444

Chemistry of Materials   Impact Factor & Quartile

0897-4756

1520-5002

Ferroptosis, a programmed cell death driven by abundant accumulation of lipid peroxides (LPO), has emerged to be an Achilles’ heel for therapy-resistant tumors. However, the curative effect is severely suppressed by insufficient LPO content and defense of intracellular antioxidant systems. Herein, we construct a drug-loaded membrane fusion liposome that can preferentially transfer fatty acid hydroperoxide to cancer cells while simultaneously blocking their agonistic antioxidant systems, thereby promptly inducing excessive LPO accumulation to trigger a “ferroptosis explosion”. Sulfasalazine (SSZ), an inhibitor of the cystine/glutamate antiporter (system xc), dominating intracellular glutathione (GSH) synthesis, is loaded in membrane fusion liposomes that are embellished with linoleic acid hydroperoxide (LAOOH) and cRGD tumor-binding peptide. The enhanced permeability and retention (EPR) effect combined with cRGD binding facilitates oxidative liposomes to selectively accumulate at the tumor upon administration, followed by abundant LAOOH and SSZ delivery to the tumor cells via the membrane fusion mechanism. The resultant instantaneous and overwhelming LPO accumulation not only induces rapid tumor cell ferroptosis but also mediates a “bystander effect” to sensitize adjacent tumor cells to subsequent therapy, bringing about superior tumor inhibition both in vitro and in vivo. Overall, our two-pronged strategy employing an oxidative liposome to rapidly stimulate excessive LPO generation and suppress oxidation defense system represents a promising approach to significantly amplify ferroptosis for treatment of drug-resistant cancer.

SCI

English

Corresponding

National Natural Science Foundation of China["52003086","21972047","82273040"] ; China Postdoctoral Science Foundation[2021T140213] ; Natural Science Foundation of Guangdong Province, China["2021A1515010724","2021A1515220051","2022A0505050008"] ; Guangdong Key Areas RD Program[2022B1111080007] ; Science and Technology Foundation of Shenzhen[JCYJ20200109144410181] ; Guangdong Provincial Pearl River Talents Program[2019QN01Y314] ; Program for Guangdong Introducing Innovative and Entrepreneurial Teams[2019ZT08Y318] ; Science and Technology Project of Guangzhou, China["202102020352","202102020259"]

Chemistry ; Materials Science

Chemistry, Physical ; Materials Science, Multidisciplinary

WOS:001004349400001

AMER CHEMICAL SOC

MATERIALS SCIENCE

2-s2.0-85163451760

Scopus

1.MOE International Joint Research Laboratory on Synthetic Biology and Medicines,School of Biology and Biological Engineering,South China University of Technology,Guangzhou,510006,China
2.The Second Affiliated Hospital,State Key Laboratory of Respiratory Disease,Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology,Guangzhou Medical University,Guangzhou,510260,China
3.Center for Micro-Engineered Materials and the Department of Chemical and Biological Engineering,The University of New Mexico,Albuquerque,87131,United States
4.Guangdong Provincial Clinical Research Center for Geriatrics,Shenzhen Clinical Research Center for Geriatrics,Shenzhen People’s Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,518055,China

Kong，Fanhui,Lei，Qi,Ma，Yi,et al. Membrane Fusion Liposome-Mediated Ferroptosis Explosion for Enhanced Cancer Therapy[J]. Chemistry of Materials,2023,35(12):4731-4742.

Kong，Fanhui.,Lei，Qi.,Ma，Yi.,He，Peiying.,Zheng，Guansheng.,...&Zhu，Wei.(2023).Membrane Fusion Liposome-Mediated Ferroptosis Explosion for Enhanced Cancer Therapy.Chemistry of Materials,35(12),4731-4742.

Kong，Fanhui,et al."Membrane Fusion Liposome-Mediated Ferroptosis Explosion for Enhanced Cancer Therapy".Chemistry of Materials 35.12(2023):4731-4742.