Endogenous macrophages as “Trojan horses” for targeted oral delivery of mRNA-encoded cytokines in tumor microenvironment immunotherapy
Journal
Biomaterials
Journal Volume
325
Start Page
123620
ISSN
1429612
Date Issued
2026
Author(s)
Luo, Po-Kai
Chang, Wan-An
Peng, Sheng-Yao
Chuang, Ya-Han
Nguyen, Lam-Duc-Huy
Guo, Jhih-Syuan
Wei, Hao-Chi
Lai, Po-Liang
Chang, Hsiao-Huang
Wang, Kuan-Lin
Chen, Yin-Hsu
Sung, Hsing-Wen
Abstract
Macrophages (MΦ) in the tumor microenvironment (TME) are often skewed toward the M2 phenotype, which suppresses immune responses and supports tumor progression. Interferon-γ (IFN-γ) plays a pivotal role in reprogramming MΦ toward a pro-inflammatory M1-like phenotype, thereby enhancing anti-tumor immunity. This study introduces a targeted oral immunotherapy strategy using IFN-γ mRNA-loaded lipid nanoparticles conjugated with β-glucans (IFN-γ mRNA@βGlus-LNPs), evaluated in a mouse model of triple-negative breast cancer. Following oral administration, the nanoparticles target transcytotic M cells in Peyer's patches, are taken up by endogenous MΦ in intestinal lymphoid tissues, and transported via lymphatic and systemic circulation to the tumor site. In the TME, the nanoparticles induce transient, localized IFN-γ expression, reprogramming both infiltrating and resident MΦ toward an M1-like phenotype and activating cytotoxic T cell responses. By harnessing the natural tumor-homing ability and biocompatibility of MΦ, this ?�Trojan horse??approach offers a promising platform for effective, safe mRNA-based cancer immunotherapy. © 2025 Elsevier Ltd
Subjects
Cellular carriers
Macrophage polarization
Oral delivery
Targeted cancer therapy
Tumor immunotherapy
Publisher
Elsevier Ltd
Type
journal article