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

Yixuan Liu, Ying Xie, Yuling Chen, Jialun Duan, Chunjie Bao, Jinling Wang, Hexuan Feng, Mengjie Wang, Yuxin Ren, Peishan Li, Qian Luo, Jiarui Xu, Min Jiang, Yanchen Men, Yang Wu, Jianwei Li, Guiling Wang and Wanliang Lu ()
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Yixuan Liu: Peking University
Ying Xie: Peking University
Yuling Chen: Peking University
Jialun Duan: Peking University
Chunjie Bao: Peking University
Jinling Wang: Peking University
Hexuan Feng: Peking University
Mengjie Wang: Peking University
Yuxin Ren: Peking University
Peishan Li: Peking University
Qian Luo: Peking University
Jiarui Xu: Peking University
Min Jiang: Peking University
Yanchen Men: Peking University
Yang Wu: Peking University
Jianwei Li: Peking University
Guiling Wang: Peking University
Wanliang Lu: Peking University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57965-6

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