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Efficacious suppression of primary and metastasized liver tumors by polyIC-loaded lipid nanoparticles

delete2025-09-01
delete1
PRE
AI
Y
Yingluo Liu
X
Xinyi Wang
N
Nishta Krishnan
H
Hsiao, Timothy
Y
Yichun Ji
K
Kota Kaneko
M
Marcos G. Teneche
P
Peter D. Adams
E
Elina I. Zúñiga
S
Susan M. Kaech
L
Liangfang Zhang
G
Gen‐Sheng Feng *
DOI：10.1097/HEP.0000000000001514delete
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Abstract

Abstract

En 中文
Background and Aims:So far, there is no effective mechanism-based therapeutic agent tailored for liver tumors. Immune checkpoint inhibitors (ICIs) have demonstrated limited efficacy in liver cancer, often associated with severe adverse effects. Although poly-inosinic:cytidylic acid (polyIC) has shown an adjuvant effect when combined with anti-PD-L1 antibody (alpha PD-L1) in treating liver tumors in animal models, its systemic toxicity limits its clinical utility. To address this challenge, the original goal of this study was to develop a liver-targeted strategy to minimize toxicity.Methods and Results:We constructed lipid nanoparticles (LNPs) encapsulating polyIC for selective delivery to the liver and evaluated the tumor-suppressive effects of polyIC-LNPs, free polyIC, and/or alpha PD-L1 in multiple murine liver tumor models. We also analyzed changes in the hepatic immune microenvironment using single-cell RNA sequencing and flow cytometry. Surprisingly, polyIC-LNPs alone robustly suppressed both primary and metastatic liver tumors, independent of alpha PD-L1. Even a single dose of polyIC-LNPs was sufficient to control liver tumor progression. Primarily taken up by hepatocytes, polyIC-LNPs induced sustained type I interferon signaling, reshaped the hepatic immune landscape, and promoted CD8+ T cell infiltration and activation by enhancing the maturation of conventional dendritic cells (cDC1), ultimately resulting in a potent antitumor response.Conclusions:Contrary to our original goal, we unexpectedly found that polyIC-LNPs function as an efficacious monotherapy tailored for liver cancer, capable of coordinately modulating antitumor immunity. This novel approach eliminates the need for ICIs, thereby addressing key limitations of current immunotherapies.
Keywords:
drug delivery
dsRNA
interferon signaling
lipid nanoparticles
liver cancer immunotherapy

Journal

Hepatology cover
Hepatology
IF:
15.8
Papers:
2.0W
Citations:
7.2W

Organization

No organization information available