2. Academic Validation
  3. Injectable celastrol-loading emulsion hydrogel for immunotherapy of low-immunogenic cancer

Injectable celastrol-loading emulsion hydrogel for immunotherapy of low-immunogenic cancer

  • J Nanobiotechnology. 2025 Mar 6;23(1):183. doi: 10.1186/s12951-025-03154-y.
Yu Liu # 1 2,  Jia Zhang # 2 3,  Chunyu Lai # 2,  Wenjun Wang # 4,  Yangyue Huang 5,  Xuanwen Bao 2 6,  Haimeng Yan 7,  Xuqi Sun 2,  Qiqi Liu 8,  Dong Chen 9 10,  Xiaomeng Dai 11 12 13,  Xinyu Qian 14,  Peng Zhao 15 16
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
  • 2 Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, China.
  • 3 College of Energy Engineering, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, 310027, China.
  • 4 Department of Plastic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 5 Department of Hepatobiliary Pancreatic Oncology, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, China.
  • 6 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
  • 7 College of Medicine, Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, Qingchun Road 79, Hangzhou, 310003, China.
  • 8 Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, China.
  • 9 Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, China. chen_dong@zju.edu.cn.
  • 10 College of Energy Engineering, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, 310027, China. chen_dong@zju.edu.cn.
  • 11 Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, China. dxm1106@zju.edu.cn.
  • 12 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. dxm1106@zju.edu.cn.
  • 13 Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China. dxm1106@zju.edu.cn.
  • 14 Department of Medical Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, China. qianxinyu@hospital.westlake.edu.cn.
  • 15 Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, China. zhaop@zju.edu.cn.
  • 16 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. zhaop@zju.edu.cn.
  • # Contributed equally.
PMID: 40050985 DOI: 10.1186/s12951-025-03154-y
Abstract

Immunotherapy, exemplified by Immune Checkpoint blockade (ICB), has been extensively employed in antitumor treatments. Nevertheless, its efficacy in addressing low-immunogenic tumors has not yielded satisfactory results, primarily due to the depletion and inadequate infiltration of effector T cells within the tumor microenvironment (TME). Here, we construct an injectable water-in-oil emulsion hydrogel to load clinically used Celastrol (Gel@Cel), which addresses the limitations of Cel's hydrophobicity. Cel can both inhibit tumor cell proliferation and promote tumor cell Apoptosis, while simultaneously inducing immunogenic cell death, through activation of the Akt and MAPK pathways. In a model of clinically refractory hepatocellular carcinoma with malignant ascites, intraperitoneal administration of Gel@Cel significantly inhibits tumor progression and activates antitumor immune effects through lipase-controlled release of Cel, as compared to free Cel. Intriguingly, the Gel@Cel induces the activation of dendritic cells, resulting in the infiltration of cytotoxic T cells in the TME of ascites. Furthermore, the administration of Cel increases the expression of programmed cell death protein ligand-1 (PD-L1) in tumor cells. Moreover, combining the PD-1 antibody (αPD-1) with Gel@Cel further enhances the antitumor effect and amplifies the immune activation. In conclusion, Gel@Cel exhibits promising therapeutic potential in the treatment of low-immunogenic tumors, especially when combined with ICB therapy.

Keywords

Celastrol; Emulsion hydrogel; Immune checkpoint blockade; Immunogenic cell death.

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