Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in vivo CAR-T therapy for inflamm-aging

  • Cell Rep Med. 2025 Jul 15;6(7):102209. doi: 10.1016/j.xcrm.2025.102209.
Zihan Zhang  1 ,  Bin Ma  1 ,  Buyao Li  1 ,  Zhiwei Li  2 ,  Min Gao  3 ,  Hailong Zhao  3 ,  Rui Peng  3 ,  Jiang Hu  4 ,  Yu Wang  5 ,  Wei You  6 ,  Xun Gui  7 ,  Rui Wang  7 ,  Xiaoqing Hu  8 ,  Beidi Chen  9 ,  Yuanjie Zhang  10 ,  Yanyun Hao  1 ,  Xiaolin Sun  11 ,  Peishi Rao  11 ,  Liang Zhang  12 ,  Ming Lu  13 ,  Demin Zhou  10 ,  Yun Yang  14 ,  Mi Deng  15 ,  Lei Miao  16
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2. State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute, Health Science Center, Peking University, Beijing 100191, China.
  • 3. State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute, Health Science Center, Peking University, Beijing 100191, China; School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China.
  • 4. Shanghai CirCode Biomed Co.,Ltd., Shanghai 200131, China.
  • 5. Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
  • 6. Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7. Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China.
  • 8. Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, Beijing 100191, China.
  • 9. Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, China.
  • 10. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 11. Department of Rheumatology and Immunology, Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China.
  • 12. Department of Orthopedics, Beijing Jishuitan Hospital, Fourth Clinical College of Peking University, Beijing, China.
  • 13. SIP LifeLink Oncology Research Institute, Suzhou 215004, China.
  • 14. Shanghai CirCode Biomed Co.,Ltd., Shanghai 200131, China. Electronic address: [email protected].
  • 15. State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute, Health Science Center, Peking University, Beijing 100191, China; Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Peking University Cancer Hospital and Institute, Peking University, Beijing 100142, China; School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 16. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China. Electronic address: [email protected].
PMID: 40602406 DOI: 10.1016/j.xcrm.2025.102209
Abstract

mRNA-based in vivo chimeric antigen receptor (CAR)-T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery methods require antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identify cardiolipin-like di-phosphoramide lipids that improve T Cell Transfection without targeting ligands, both in vitro and in vivo. The T cell-favored tropism is likely due to the lipid's packing, shape, and rigidity. Encapsulating circular RNA further prolongs mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we deliver mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single-cell Sequencing in humans confirms uPAR's relevance to senescence and inflammation in RA. To facilitate clinical translation, we screen and humanize single-chain variable fragments (scFvs) against uPAR, establishing a PL40 mRNA-encoded humanized uPAR CAR with potential for treating aging-inflamed disorders.

Keywords
T cells; aging-inflamed disorders; chimeric antigen receptor: CAR; circular mRNA; senolytic; uPAR.