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Endogenous macrophages as "Trojan horses" for targeted oral delivery of mRNA-encoded cytokines in tumor microenvironment immunotherapy

Luo, Po-Kai, Chang, Wan-An, Peng, Sheng-Yao, Chu, Li-An, 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·2026·Biomaterials
DOI 10.1016/j.biomaterials.2025.123620
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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.

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Metadata

Authors
Luo, P.-K., Chang, W.-A., Peng, S.-Y., Chu, L.-A., Chuang, Y.-H., Nguyen, L.-D.-H., Guo, J.-S., Wei, H.-C., Lai, P.-L., Chang, H.-H., Wang, K.-L., Chen, Y.-H., & Sung, H.-W.
Venue
Biomaterials
Publisher
Elsevier BV
Published
2026-02
Volume
325
Pages
123620
ISSN
0142-9612
DOI
10.1016/j.biomaterials.2025.123620
Cited by
10
References
1
Language
en
Licence
Funders
  • Academia Sinica (AS\u2013CFII\u2013111-210, AS-KPQ-109-TPP2)
  • Ministry of Education
  • National Science and Technology Council (113-2639-E-007-001- ASP)

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