Dual asparagine-depriving nanoparticles against solid tumors

Yubo Shen, Huifang Wang, Daoxia Guo, Jiantao Liu, Jinli Sun, Nan Chen (), Haiyun Song () and Xiaoyuan Ji ()
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Yubo Shen: Shanghai Jiao Tong University School of Medicine
Huifang Wang: Shanghai Jiao Tong University School of Medicine
Daoxia Guo: Shanghai Jiao Tong University School of Medicine
Jiantao Liu: Shanghai Normal University
Jinli Sun: Shanghai Jiao Tong University School of Medicine
Nan Chen: Shanghai Normal University
Haiyun Song: Shanghai Jiao Tong University School of Medicine
Xiaoyuan Ji: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Depletion of circulatory asparagine (Asn) by L-asparaginase (ASNase) has been used for clinical treatment of leukemia, whereas solid tumors are unresponsive to this therapy owing to their active Asn biosynthesis. Herein, we develop a type of core-shell structured cascade-responsive nanoparticles (NPs) for sequential modulation of exogenous Asn supply and endogenous Asn production. The reactive oxygen species-sensitive NP shells disintegrate in the tumor microenvironment and liberate ASNase to scavenge extracellular Asn. The acid-labile NP cores subsequently decompose in the tumor cells and release rotenone to block intracellular Asn biosynthesis. Administration of the dual Asn-depriving NPs in murine models of triple-negative breast cancer and colorectal cancer substantially suppress the growth and epithelial-mesenchymal transition of primary and relapsed tumors, fully eradicate spontaneous and post-surgical metastasis, and confer long-term T cell memory for complete resistance to tumor rechallenge. This study represents a generalized strategy to harness amino acid depletion therapy against solid tumors.

Date: 2025
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DOI: 10.1038/s41467-025-60798-y

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