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作者

Zhongjie Tang Tongcheng Dai Shiqiong Wu Xiaoyi Chen Binhua Lv Dawei Cui Ranran Luo Huaxing Zhan Yun Liu Yixuan Tang Chong Li

作者单位

⁴Suzhou Zelgen Biopharmaceuticals Co., Ltd., Kunshan 215300, China ⁶Department of Radiology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China ⁷Xiamen Ginposome Pharmaceutical Co., Ltd., Xiamen 361026, China ³These authors contributed equally to this work. ¹School of Pharmaceutical Sciences & Institute of Materia Medica, Medical Science and Technology Innovation Center, Key Laboratory for Biotechnology Drugs of National Health Commission, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China ⁵Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China ²Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China

刊名

Journal of Controlled Release

年份

2025

页码

114320

ISSN

0168-3659

摘要

Hepatocellular carcinoma remains a major global health challenge with limited therapeutic options. Liver-resident Kupffer cells, which exhibit strong phagocytic activity and predominantly adopt an immunosuppressive M2 phenotype in the tumor microenvironment, not only promote tumor immune escape but also rapidly clear conventional drug delivery systems, posing a fundamental barrier to effective treatment. Herein, we present a novel strategy that uses these cells as both barriers and therapeutic ...更多

Hepatocellular carcinoma remains a major global health challenge with limited therapeutic options. Liver-resident Kupffer cells, which exhibit strong phagocytic activity and predominantly adopt an immunosuppressive M2 phenotype in the tumor microenvironment, not only promote tumor immune escape but also rapidly clear conventional drug delivery systems, posing a fundamental barrier to effective treatment. Herein, we present a novel strategy that uses these cells as both barriers and therapeutic anchors. We developed a CD47-mimetic self-peptide-modified liposomal system that targets SIRPα on Kupffer cells and delivers the TLR8 agonist ZG0895, currently in clinical trials in the U.S. and China. By activating “don't-eat-me” signaling, the system suppresses phagocytosis, enabling stable surface attachment and sustained release of the agonist for durable immune reprogramming. Importantly, this phagocytosis inhibition establishes a spatiotemporal window that facilitates co-delivery of doxorubicin liposomes to HCC cells via GLUT1-mediated targeting, resulting in synergistic immunochemotherapeutic effects. This dual modulation strategy improves targeting precision, treatment durability, and therapeutic synergy, offering a unique intrahepatic approach that addresses key challenges in HCC management and accelerates the clinical translation of TLR8 agonist–based nanomedicines.收起

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