用于对抗实体瘤的双天冬酰胺剥夺纳米颗粒。

Dual asparagine-depriving nanoparticles against solid tumors.

作者信息

Shen Yubo, Wang Huifang, Guo Daoxia, Liu Jiantao, Sun Jinli, Chen Nan, Song Haiyun, Ji Xiaoyuan

机构信息

School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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.

出版信息

Nat Commun. 2025 Jul 1;16(1):5675. doi: 10.1038/s41467-025-60798-y.

DOI:10.1038/s41467-025-60798-y

PMID:40593710

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.

摘要

L-天冬酰胺酶（ASNase）消耗循环中的天冬酰胺（Asn）已被用于白血病的临床治疗，而实体瘤由于其活跃的Asn生物合成对该疗法无反应。在此，我们开发了一种核壳结构的级联响应纳米颗粒（NPs），用于对外源Asn供应和内源性Asn产生进行顺序调节。对活性氧敏感的NP壳在肿瘤微环境中分解并释放ASNase以清除细胞外Asn。随后，对酸不稳定的NP核在肿瘤细胞中分解并释放鱼藤酮以阻断细胞内Asn生物合成。在三阴性乳腺癌和结直肠癌的小鼠模型中施用双重Asn剥夺NP可显著抑制原发性和复发性肿瘤的生长和上皮-间质转化，完全根除自发性和手术后转移，并赋予长期T细胞记忆以完全抵抗肿瘤再挑战。这项研究代表了一种利用氨基酸消耗疗法对抗实体瘤的通用策略。