Interleukin 15-Presenting Nanovesicles with Doxorubicin-Loaded Ferritin Cores for Cancer Immunochemotherapy

Yihui Zhai; Wen Zhang; Jinming Wang; Ying Kong; Rong Rong; Tianqun Lang; Chao Zheng; Yanke Wang; Yang Yu; Helen He Zhu; Ying Cai; Pengcheng Zhang; Yaping Li

doi:10.1002/advs.202409194

Interleukin 15-Presenting Nanovesicles with Doxorubicin-Loaded Ferritin Cores for Cancer Immunochemotherapy

Adv Sci (Weinh). 2024 Dec 3:e2409194. doi: 10.1002/advs.202409194. Online ahead of print.

Authors

Yihui Zhai^{1

2}, Wen Zhang^{3

4}, Jinming Wang⁵, Ying Kong⁶, Rong Rong⁶, Tianqun Lang^{1

2}, Chao Zheng^{3

4}, Yanke Wang⁷, Yang Yu⁷, Helen He Zhu⁵, Ying Cai^{1

2

8}, Pengcheng Zhang^{9

10}, Yaping Li^{1

2

8}

Affiliations

¹ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
² University of Chinese Academy of Sciences, Beijing, 100049, China.
³ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ China State Institute of Pharmaceutical Industry, Shanghai, 201203, China.
⁵ State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁶ Yantai Institute of Materia Medica, Shandong, 264000, China.
⁷ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, 201210, China.
⁸ Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
⁹ School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, 201210, China.
¹⁰ Shanghai Clinical Research and Trial Center, Shanghai, 201203, China.

PMID: 39625860
DOI: 10.1002/advs.202409194

Abstract

Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non-specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin-loaded ferritin (Dox-Fn) are reported. The DoxFILN significantly enhances the densities and activities of intratumoral CTLs and NK cells. Mechanistically, DoxFILN undergoes deshelling in the acidic tumor microenvironment, releasing Dox-Fn and membrane-bound IL15c. Dox-Fn selectively target transferrin receptors on cancerous cells, facilitating intracellular Dox release and inducing immunogenic cell death. Concurrently, membrane-bound IL15c recognizes and activates IL15 receptor β/γc heterodimers, leading to a remarkable increase in the proliferation and activation of CTLs (16-fold and 28-fold) and NK cells (37-fold and 50-fold). The IL15-displaying nanovesicle introduced here holds promise as a potential platform for immunochemotherapy in the treatment of cancer.

Keywords: CTLs; IL15, immunotherapy; NK cells; nanovesicles.

Abstract

Grants and funding