Liposomes embedded with PEGylated iron oxide nanoparticles enable ferroptosis and combination therapy in cancer

Yang Liu; Xuebo Quan; Jie Li; Jiawei Huo; Xing Li; Zhongpu Zhao; Shumu Li; Jing Wan; Jiao Li; Shuai Liu; Tao Wang; Xing Zhang; Bo Guan; Rui Wen; Zhenwen Zhao; Chunru Wang; Chunli Bai

doi:10.1093/nsr/nwac167

Liposomes embedded with PEGylated iron oxide nanoparticles enable ferroptosis and combination therapy in cancer

Natl Sci Rev. 2022 Aug 18;10(1):nwac167. doi: 10.1093/nsr/nwac167. eCollection 2023 Jan.

Authors

Yang Liu^{1

2}, Xuebo Quan³, Jie Li¹, Jiawei Huo^{1

2}, Xing Li^{2

4}, Zhongpu Zhao^{1

2}, Shumu Li¹, Jing Wan^{1

2}, Jiao Li¹, Shuai Liu¹, Tao Wang¹, Xing Zhang¹, Bo Guan¹, Rui Wen¹, Zhenwen Zhao^{2

4}, Chunru Wang^{1

2}, Chunli Bai^{1

2}

Affiliations

¹ Beijing National Research Center for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China.
⁴ Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing Mass Spectrum Center, Beijing 100190, China.

Abstract

Ferroptosis, an iron-dependent regulated cell death process driven by excessive lipid peroxides, can enhance cancer vulnerability to chemotherapy, targeted therapy and immunotherapy. As an essential upstream process for ferroptosis activation, lipid peroxidation of biological membranes is expected to be primarily induced by intrabilayer reactive oxygen species (ROS), indicating a promising strategy to initiate peroxidation by improving the local content of diffusion-limited ROS in the lipid bilayer. Herein, liposomes embedded with PEG-coated 3 nm γ-Fe₂O₃ nanoparticles in the bilayer (abbreviated as Lp-IO) were constructed to promote the intrabilayer generation of hydroxyl radicals (•OH) from hydrogen peroxide (H₂O₂), and the integration of amphiphilic PEG moieties with liposomal bilayer improved lipid membrane permeability to H₂O₂ and •OH, resulting in efficient initiation of lipid peroxidation and thus ferroptosis in cancer cells. Additionally, Lp-IO enabled traceable magnetic resonance imaging and pH/ROS dual-responsive drug delivery. Synergistic antineoplastic effects of chemotherapy and ferroptosis, and alleviated chemotherapeutic toxicity, were achieved by delivering doxorubicin (capable of xCT and glutathione peroxidase inhibition) with Lp-IO. This work provides an efficient alternative for triggering therapeutic lipid peroxidation and a ferroptosis-activating drug delivery vehicle for combination cancer therapies.

Keywords: combination therapy; ferroptosis; intrabilayer lipid peroxidation; liposome; ultrasmall iron oxide nanoparticles.