2. Academic Validation
  3. Dual asparagine-depriving nanoparticles against solid tumors

Dual asparagine-depriving nanoparticles against solid tumors

  • Nat Commun. 2025 Jul 1;16(1):5675. doi: 10.1038/s41467-025-60798-y.
Yubo Shen # 1,  Huifang Wang # 1,  Daoxia Guo 1,  Jiantao Liu 2,  Jinli Sun 1,  Nan Chen 3,  Haiyun Song 4,  Xiaoyuan Ji 5
Affiliations

Affiliations

  • 1 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 College of Chemistry and Materials Science, The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Normal University, Shanghai, China.
  • 3 College of Chemistry and Materials Science, The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Normal University, Shanghai, China. nchen@shnu.edu.cn.
  • 4 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. songhaiyun@shsmu.edu.cn.
  • 5 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. xyji@shsmu.edu.cn.
  • # Contributed equally.
PMID: 40593710 DOI: 10.1038/s41467-025-60798-y
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.

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