A protease-cleavable liposome for co-delivery of anti-PD-L1 and doxorubicin for colon cancer therapy in mice

  • Nat Commun. 2025 Mar 24;16(1):2854. doi: 10.1038/s41467-025-57965-6.
Yixuan Liu  #  1  2 ,  Ying Xie  #  1  2 ,  Yuling Chen  1  2 ,  Jialun Duan  1  2 ,  Chunjie Bao  1  2 ,  Jinling Wang  1  2 ,  Hexuan Feng  1  2 ,  Mengjie Wang  1  2 ,  Yuxin Ren  1  2 ,  Peishan Li  1  2 ,  Qian Luo  1  2 ,  Jiarui Xu  1  2 ,  Min Jiang  1  2 ,  Yanchen Men  1  2 ,  Yang Wu  1  2 ,  Jianwei Li  1  2 ,  Guiling Wang  1  2 ,  Wanliang Lu  3  4
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100191, Beijing, China.
  • 2. Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, 100191, Beijing, China.
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100191, Beijing, China. [email protected].
  • 4. Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, 100191, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 40128211 DOI: 10.1038/s41467-025-57965-6
Abstract

Immune checkpoint blockade therapy using programmed cell death 1 (PD1) or programmed death ligand 1 (PD-L1) has made significant progress in the treatment of advanced cancers, with some patients achieving long-term remission without clinical recurrence. However, only a minority of colon Cancer patients respond to the therapy. Here, we report a protease-cleavable anti-PD-L1 antibody Liposome, eLipo anti-PD-L1, for enhancing colon Cancer therapy. In vivo, eLipo anti-PD-L1 is cleaved by Legumain at colon Cancer site into pegylated anti-PD-L1 and cancer-homing doxorubicin Liposome. Functional assessments show cancer-targeting, legumain-responding, tumor-penetrating, and immune-activating effects, as well as efficacy in treating colon cancer-bearing mice in vivo. Further mechanistic analysis implicates genes related to T cell differentiation and T cell receptor signaling as potential molecular mediators. Lastly, human colorectal Cancer tissue evaluations verify expressions of PD-L1 and Legumain, hinting a potential translatability. Our study thus suggests that eLipo anti-PD-L1 may be a feasible vector for co-delivery of immunochemotherapy for colon Cancer.

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