Induction of Tumor Ferroptosis-Dependent Immunity via an Injectable Attractive Pickering Emulsion Gel

Xiaomeng Dai; Jia Zhang; Xuanwen Bao; Yixuan Guo; Yuzhi Jin; Chenjing Yang; Hangyu Zhang; Lulu Liu; Yang Gao; Chanqi Ye; Wei Wu; Chuan Liu; Chun-Xia Zhao; Jianpeng Sheng; En Ren; Hongjun Li; Weijia Fang; Baiheng Wu; Jian Ruan; Zhen Gu; Dong Chen; Peng Zhao

doi:10.1002/adma.202303542

Induction of Tumor Ferroptosis-Dependent Immunity via an Injectable Attractive Pickering Emulsion Gel

Adv Mater. 2023 Sep;35(35):e2303542. doi: 10.1002/adma.202303542. Epub 2023 Jul 24.

Authors

Xiaomeng Dai¹, Jia Zhang^{1

2}, Xuanwen Bao¹, Yixuan Guo¹, Yuzhi Jin¹, Chenjing Yang^{1

2}, Hangyu Zhang¹, Lulu Liu¹, Yang Gao¹, Chanqi Ye¹, Wei Wu¹, Chuan Liu¹, Chun-Xia Zhao³, Jianpeng Sheng⁴, En Ren⁵, Hongjun Li^{5

6

7

8}, Weijia Fang¹, Baiheng Wu⁹, Jian Ruan^{1

10}, Zhen Gu^{5

6

7

11

12}, Dong Chen^{1

2}, Peng Zhao¹

Affiliations

¹ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P. R. China.
² College of Energy Engineering and State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, 310027, China.
³ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia.
⁴ The First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310027, China.
⁵ Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁶ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
⁷ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
⁸ Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
⁹ College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, 311121, China.
¹⁰ Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
¹¹ Jinhua Institute of Zhejiang University, Jinhua, 321299, China.
¹² Department of General Surgery, Sir Run Run Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.

PMID: 37192546
DOI: 10.1002/adma.202303542

Abstract

The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water-in-oil Pickering emulsion gel is developed to deliver (1S, 3R)-RSL-3 (RSL-3), a ferroptosis inducer dissolved in iodized oil, and programmed death-1 (PD-1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL-3 + PD-1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL-3 and PD-1 antibody and a notable antitumor effect against low-immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL-3 + PD-1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single-cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.

Keywords: cancer immunotherapy; drug delivery; ferroptosis; immune checkpoint blockade.

Abstract

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