Luo, Po-KaiPo-KaiLuoChang, Wan-AnWan-AnChangPeng, Sheng-YaoSheng-YaoPengLI-AN CHUChuang, Ya-HanYa-HanChuangNguyen, Lam-Duc-HuyLam-Duc-HuyNguyenGuo, Jhih-SyuanJhih-SyuanGuoWei, Hao-ChiHao-ChiWeiLai, Po-LiangPo-LiangLaiChang, Hsiao-HuangHsiao-HuangChangWang, Kuan-LinKuan-LinWangChen, Yin-HsuYin-HsuChenSung, Hsing-WenHsing-WenSung2026-03-242026-03-242026https://www.scopus.com/inward/record.uri?eid=2-s2.0-105012978352&doi=10.1016%2Fj.biomaterials.2025.123620&partnerID=40&md5=257cb0765c6d014a7f232589442a9a79https://scholars.lib.ntu.edu.tw/handle/123456789/736658Macrophages (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 LtdCellular carriersMacrophage polarizationOral deliveryTargeted cancer therapyTumor immunotherapyjournal article10.1016/j.biomaterials.2025.1236202-s2.0-105012978352