2. Academic Validation
  3. IL-21 Loading CaMnCO3 Vitality Backpacks Boost CAR-T Cell Synergistic Immunotherapy

IL-21 Loading CaMnCO3 Vitality Backpacks Boost CAR-T Cell Synergistic Immunotherapy

  • Small. 2025 Jun;21(25):e2501645. doi: 10.1002/smll.202501645.
Baihui Wang 1 2,  Yuchan Xue 1,  Yang Jia 3,  Yuyao Duan 4,  Dejun Li 5,  Minghao Sui 1,  Yuemin Feng 1,  Le Wang 1,  Han Ding 1,  Xinyu Wang 1,  Tianru Zhang 1,  Yanning Sun 6,  Huimin Liu 7,  Jianni Qi 7,  Jiazhi Duan 8,  Songbo Zhao 7,  Qiang Zhu 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
  • 2 Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266001, P. R. China.
  • 3 Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
  • 4 Reproductive Medical Center, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250012, P. R. China.
  • 5 Department of ICU, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
  • 6 Urology Department, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, P. R. China.
  • 7 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
  • 8 Institute for Advanced Interdisciplinary Research, University of Jinan, Jinan, 250022, P. R. China.
  • 9 Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
PMID: 40345978 DOI: 10.1002/smll.202501645
Abstract

Chimeric antigen receptor (CAR)-T-cell therapy achieves considerable success in the treatment of malignant tumors, but clinical relapse due to the tumor microenvironment (TME) is very common. The TME of solid tumors is characterized by weak acidity, hypoxia, and elevated Reactive Oxygen Species (ROS) levels, which collectively impair the function and persistence of infiltrating CAR-T cells. In this study, acid-sensitive responsive CaMnCO3 nanoparticles (CMC NPs), are developed that simultaneously mitigate TME acidosis and hypoxia. IL-21 is encapsulated within CMC NPs (denoted as CMC-21), which are then surface-conjugated to CAR-T cells as functional 'vitality backpacks' to enhance cellular activity. The CMC-21 backpack enables sustained release of IL-21, persistently enhancing CAR-T cell antitumor immunity across both low- and high-dose infusion regimens. Furthermore, CMC NPs exert dual modulatory effects on the TME by: 1) consuming protons to neutralize acidic conditions, and 2) catalytically converting endogenous H2O2 to O2 to relieve hypoxia. This multimodal remodeling of the immunosuppressive TME significantly enhances the infiltration and activity of adoptively transferred CAR-T cells while simultaneously boosting endogenous T cell and NK cell recruitment in vivo. These findings establish a novel CAR-T cell enhancement strategy through sustained IL-21 release from CMC-21 backpacks, offering new possibilities for solid tumor immunotherapy.

Keywords

CAR‐T cell; hepatocellular carcinoma; immunoactivation; tumor microenvironment; vitality backpacks.

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