Nano-hydrogel-based delivery system for dihydroartemisinin to enhance cuproptosis and synergize with anti-PD-1 therapy in triple-negative breast cancer

Journal of Nanobiotechnology

卷:24

Research

Qiaoli Yi^1,2  Fada Xia³  Tong-Fei Li⁴  Jiayu Wang¹  Liu-Gen Li⁴  Fengyu Tan¹  Xia Wang¹  Hailin Tang⁵  Wangrui Liu⁶  Zhijie Xu²  Fan Leng⁴  Xiaokang Wang⁷  Yuanliang Yan¹ 

[1] Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China

[2] Department of Pharmacy, Shenzhen Longhua District Central Hospital, the Affiliated Longhua Hospital of Shenzhen University, 518000, Shenzhen, Guangdong, China

[3] Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, 442000, Shiyan, Hubei, China

[4] Department of Pharmacy, National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Xiangya Hospital, The Hunan Institute of Pharmacy Practice and Clinical Research, Central South University, 410008, Changsha, China

[5] State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 510050, Guangzhou, Guangdong, China

[6] Department of Pathology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China

[7] Department of Thyroid Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China

关键词: Triple-negative breast cancer;    Nanocomposite hydrogel;    Dihydroartemisinin;    Cuproptosis;    Tumor microenvironment;    T cells;    Immunotherapy;   

DOI  :  10.1186/s12951-026-04762-y

 received in 2026-03-07, accepted in 2026-06-24,  发布年份 2026

来源: Springer

【 摘 要 】

As an aggressive subtype of breast cancer, triple-negative breast cancer (TNBC) displays limited therapeutic options and poor clinical prognosis. Thus, there is an urgent need for developing more effective treatment strategies to optimize the clinical management of TNBC. Dihydroartemisinin (DHA), one kind of artemisinin derivatives, exhibits promising antitumor activity mainly through inducing excessive generation of reactive oxygen species (ROS). However, some intrinsic disadvantages, including poor aqueous solubility, short circulation time, and low bioavailability, greatly limit its clinical application. In this research, we constructed an injectable pH/ROS-responsive composite hydrogel (Lip-DHA-CuS@Gel) co-loaded with liposomal DHA (Lip-DHA) and copper sulfide (CuS) nanoparticles to enhance the therapeutic efficacy against TNBC. The hydrogel system could serve as a localized drug depot, enabling sustained drug release and improved tumor retention. In the tumor microenvironment, Lip-DHA-CuS@Gel facilitated efficient intratumoral delivery of DHA and CuS, resulting in mitochondrial copper overload and increased ROS production, thereby synergistically inducing cuproptosis. Copper chelators tetrathiomolybdate (TTM) and D-penicillamine (DPA) could significantly reverse the antitumor effects of Lip-DHA-CuS@Gel in TNBC. In the 4T1 tumor-bearing BALB/c mice, Lip-DHA-CuS@Gel synergistically potentiated the antitumor immunity of PD-1 blockade by inducing the release of damage-associated molecular patterns (DAMPs) and promoting intra-tumoral infiltration of CD8⁺ T cells. Taken together, these findings suggested that Lip-DHA-CuS@Gel highlights significant therapeutic potential to induce cuproptosis and enhance immunotherapy responsiveness in TNBC.Graphical Abstract

【 授权许可】

CC BY-NC-ND   
© The Author(s) 2026

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