CoChat
Sign Up
Cited by 10

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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
Open this paper in CoChat — free account

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.

Overview

Integrity signals

Registry

Crossref · 10.1016/j.biomaterials.2025.123620

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 1 references

Research works printed but not linked: 72

  1. Kloosterman, 2023, Macrophages at the interface of the co-evolving cancer ecosystem, Cell, 186, 1627, 10.1016/j.cell.2023.02.020 · DOI
  2. Wynn, 2013, Macrophage biology in development, homeostasis and disease, Nature, 496, 445, 10.1038/nature12034 · DOI · Paper page
  3. Chen, 2023, Macrophages in immunoregulation and therapeutics, Signal Transduct. Target. Ther., 8, 207, 10.1038/s41392-023-01452-1 · DOI
  4. Xia, 2020, Engineering macrophages for cancer immunotherapy and drug delivery, Adv. Mater., 32, 10.1002/adma.202002054 · DOI · Paper page
  5. Jorgovanovic, 2020, Roles of IFN-γ in tumor progression and regression: a review, Biomark. Res., 8, 49, 10.1186/s40364-020-00228-x · DOI · Paper page
  6. Haabeth, 2011, Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer, Nat. Commun., 2, 240, 10.1038/ncomms1239 · DOI
  7. Shao, 2023, KERS-inspired nanostructured mineral coatings boost IFN-γ mRNA therapeutic index for antitumor immunotherapy, Adv. Mater., 35
  8. Xue, 2024, Proinflammatory polarization of engineered heat-inducible macrophages reprogram the tumor immune microenvironment during cancer immunotherapy, Nat. Commun., 15, 2270, 10.1038/s41467-024-46210-1 · DOI
  9. Kang, 2021, Nanocomplex-mediated in vivo programming to chimeric antigen receptor-M1 macrophages for cancer therapy, Adv. Mater., 33, 10.1002/adma.202103258 · DOI
  10. Zheng, 2024, Engineered bacterial biomimetic vesicles reprogram tumor-associated macrophages and remodel tumor microenvironment to promote innate and adaptive antitumor immune responses, ACS Nano, 18, 6863, 10.1021/acsnano.3c06987 · DOI
  11. Yuba, 2015, pH-sensitive polymer-liposome-based antigen delivery systems potentiated with interferon-γ gene lipoplex for efficient cancer immunotherapy, Biomaterials, 67, 214, 10.1016/j.biomaterials.2015.07.031 · DOI
  12. Gocher, 2022, Interferon-γ: teammate or opponent in the tumour microenvironment?, Nat. Rev. Immunol., 22, 158, 10.1038/s41577-021-00566-3 · DOI
  13. Zhang, 2018, Nanoparticle-laden macrophages for tumor-tropic drug delivery, Adv. Mater., 30, 10.1002/adma.201805557 · DOI
  14. Chen, 2023, Macrophage-hitchhiked orally administered β-glucans-functionalized nanoparticles as “precision-guided stealth missiles” for targeted pancreatic cancer therapy, Adv. Mater., 35, 10.1002/adma.202304735 · DOI
  15. Dai, 2021, Precise control of customized macrophage cell robot for targeted therapy of solid tumors with minimal invasion, Small, 17
  16. Huang, 2021, Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer, Nat. Commun., 12, 4310, 10.1038/s41467-021-24564-0 · DOI
  17. Nguyen, 2024, Inflammation-activated endogenous macrophage-mediated prodrug delivery system overcoming biological barriers for enhanced oral meningitis therapy, Adv. Funct. Mater., 34, 10.1002/adfm.202401570 · DOI
  18. Joeris, 2017, Diversity and functions of intestinal mononuclear phagocytes, Mucosal Immunol., 10, 845, 10.1038/mi.2017.22 · DOI
  19. Bonnardel, 2015, Innate and adaptive immune functions of Peyer's patch monocyte-derived cells, Cell Rep., 11, 770, 10.1016/j.celrep.2015.03.067 · DOI
  20. Ren, 2023, Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer, Nat. Commun., 14, 7021, 10.1038/s41467-023-42883-2 · DOI
  21. Xiao, 2022, Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy, Nat. Commun., 13, 758, 10.1038/s41467-022-28279-8 · DOI
  22. Liu, 2023, mRNA-based cancer therapeutics, Nat. Rev. Cancer, 23, 526, 10.1038/s41568-023-00586-2 · DOI · Paper page
  23. Chen, 2022, Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response, Proc. Natl. Acad. Sci. U. S. A., 119, 10.1073/pnas.2207841119 · DOI
  24. Wawra, 2016, The fungal-specific β-glucan-binding lectin FGB1 alters cell-wall composition and suppresses glucan-triggered immunity in plants, Nat. Commun., 7, 10.1038/ncomms13188 · DOI
  25. Sousa, 2023, β-Glucan extracts as high-value multifunctional ingredients for skin health: a review, Carbohydr. Polym., 322, 10.1016/j.carbpol.2023.121329 · DOI
  26. Rochereau, 2021, NOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn's disease, Nat. Commun., 12, 261, 10.1038/s41467-020-20348-0 · DOI
  27. Deerhake, 2021, Emerging roles of Dectin-1 in noninfectious settings and in the CNS, Trends Immunol., 42, 891, 10.1016/j.it.2021.08.005 · DOI
  28. Mohammapdour, 2022, Mechanisms of immune response to inorganic nanoparticles and their degradation products, Adv. Drug Del. Rev., 180, 10.1016/j.addr.2021.114022 · DOI
  29. Wang, 2019, Liposomes with cyclic RGD peptide motif triggers acute immune response in mice, J. Control. Release, 293, 201, 10.1016/j.jconrel.2018.12.003 · DOI · Paper page
  30. Guth-Metzler, 2023, Goldilocks and RNA: where Mg2+ concentration is just right, Nucleic Acids Res., 51, 3529, 10.1093/nar/gkad124 · DOI
  31. Söyler, 2018, Sustainable succinylation of cellulose in a CO2-based switchable solvent and subsequent passerini 3-CR and ugi 4-CR modification, Green Chem., 20, 214, 10.1039/C7GC02577G · DOI
  32. Hwang, 2018, Functional silica nanoparticles conjugated with beta-glucan to deliver anti-tuberculosis drug molecules, J. Ind. Eng. Chem., 58, 376, 10.1016/j.jiec.2017.09.051 · DOI
  33. Singh, 2021, Therapeutic gene silencing using targeted lipid nanoparticles in metastatic ovarian cancer, Small, 17
  34. Kim, 2021, Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver, Sci. Adv., 7, 10.1126/sciadv.abf4398 · DOI
  35. Melamed, 2023, Ionizable lipid nanoparticles deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer, Sci. Adv., 9, eade1444, 10.1126/sciadv.ade1444 · DOI
  36. Xu, 2019, Exploitation of synthetic mRNA to drive immune effector cell recruitment and functional reprogramming in vivo, J. Immunol., 202, 608, 10.4049/jimmunol.1800924 · DOI
  37. Kampel, 2021, Therapeutic inhibitory RNA in head and neck cancer via functional targeted lipid nanoparticles, J. Control. Release, 337, 378, 10.1016/j.jconrel.2021.07.034 · DOI
  38. Cao, 2023, Dendritic cell-mimicking nanoparticles promote mRNA delivery to lymphoid organs, Adv. Sci., 10, 10.1002/advs.202302423 · DOI
  39. Hu, 2024, Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming, Proc. Natl. Acad. Sci. U. S. A., 121, 10.1073/pnas.2400194121 · DOI
  40. Luozhong, 2022, Phosphatidylserine lipid nanoparticles promote systemic RNA delivery to secondary lymphoid organs, Nano Lett., 22, 8304, 10.1021/acs.nanolett.2c03234 · DOI
  41. Liu, 2022, Promoting cardiac repair through simple engineering of nanoparticles with exclusive targeting capability toward myocardial reperfusion injury by thermal resistant microfluidic platform, Adv. Funct. Mater., 32
  42. Thomas, 2023, Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice, Nat. Commun., 14, 6330, 10.1038/s41467-023-41771-z · DOI
  43. Chen, 2021, Pollen-mimetic metal–organic frameworks with tunable spike-like nanostructures that promote cell interactions to improve antigen-specific humoral immunity, ACS Nano, 15, 7596, 10.1021/acsnano.1c01129 · DOI
  44. Verbeke, 2022, Innate immune mechanisms of mRNA vaccines, Immunity, 55, 1993, 10.1016/j.immuni.2022.10.014 · DOI
  45. Yasar, 2018, Kinetics of mRNA delivery and protein translation in dendritic cells using lipid-coated PLGA nanoparticles, J. Nanobiotechnol., 16, 72, 10.1186/s12951-018-0401-y · DOI
  46. Yu, 2024, OX40L-expressing M1-like macrophage exosomes for cancer immunotherapy, J. Control. Release, 365, 469, 10.1016/j.jconrel.2023.11.051 · DOI
  47. Qi, 2011, Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans, Blood, 117, 6825, 10.1182/blood-2011-02-339812 · DOI
  48. Sheng, 2024, A twindrive precise delivery system of platelet-neutrophil hybrid membrane regulates macrophage combined with CD47 blocking for postoperative immunotherapy, ACS Nano, 18, 4981, 10.1021/acsnano.3c10862 · DOI
  49. Zhang, 2022, Immunomodulatory microneedle patch for periodontal tissue regeneration, Matter, 5, 666, 10.1016/j.matt.2021.11.017 · DOI
  50. Xiao, 2024, Supramolecular peptide amphiphile nanospheres reprogram tumor-associated macrophage to reshape the immune microenvironment for enhanced breast cancer immunotherapy, Small, 20, 10.1002/smll.202307390 · DOI
  51. Tang, 2023, pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy, Nat. Commun., 14, 5888, 10.1038/s41467-023-41592-0 · DOI
  52. Zhang, 2019, Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers, Nat. Commun., 10, 3974, 10.1038/s41467-019-11911-5 · DOI
  53. Wang, 2022, Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms, Acta Pharm. Sin. B, 12, 1432, 10.1016/j.apsb.2021.08.014 · DOI
  54. He, 2018, Biomimetic thiamine- and niacin-decorated liposomes for enhanced oral delivery of insulin, Acta Pharm. Sin. B, 8, 97, 10.1016/j.apsb.2017.11.007 · DOI
  55. Ma, 2024, Mulberry leaf lipid nanoparticles: a naturally targeted CRISPR/Cas9 oral delivery platform for alleviation of colon diseases, Small, 20, 10.1002/smll.202307247 · DOI
  56. Cheng, 2023, Induction of bleb structures in lipid nanoparticle formulations of mRNA leads to improved transfection potency, Adv. Mater., 35, 10.1002/adma.202303370 · DOI
  57. Wang, 2009, Influence of micro-well biomimetic topography on intestinal epithelial Caco-2 cell phenotype, Biomaterials, 30, 6825, 10.1016/j.biomaterials.2009.08.046 · DOI
  58. Ding, 2021, Differentiated Caco-2 cell models in food-intestine interaction study: current applications and future trends, Trends Food Sci. Technol., 107, 455, 10.1016/j.tifs.2020.11.015 · DOI
  59. Wang, 2024, Insights into oral lentinan immunomodulation: dectin-1-mediated lymphatic transport from Peyer's patch M cells to mononuclear phagocytes, Carbohydr. Polym., 346, 10.1016/j.carbpol.2024.122586 · DOI
  60. Thanki, 2019, Mechanistic profiling of the release kinetics of siRNA from lipidoid-polymer hybrid nanoparticles in vitro and in vivo after pulmonary administration, J. Control. Release, 310, 82, 10.1016/j.jconrel.2019.08.004 · DOI
  61. Mitchell, 2017, Engineering and physical sciences in oncology: challenges and opportunities, Nat. Rev. Cancer, 17, 659, 10.1038/nrc.2017.83 · DOI · Paper page
  62. Blanco, 2015, Principles of nanoparticle design for overcoming biological barriers to drug delivery, Nat. Biotechnol., 33, 941, 10.1038/nbt.3330 · DOI · Paper page
  63. Nayer, 2024, Local administration of regulatory T cells promotes tissue healing, Nat. Commun., 15, 7863, 10.1038/s41467-024-51353-2 · DOI
  64. Harbeck, 2019, Breast cancer, Nat. Rev. Dis. Primers, 5, 66, 10.1038/s41572-019-0111-2 · DOI · Paper page
  65. Miao, 2021, Engineering nano- and microparticles as oral delivery vehicles to promote intestinal lymphatic drug transport, Adv. Mater., 33, 10.1002/adma.202104139 · DOI
  66. Ren, 2023, The feasibility of oral targeted drug delivery: gut immune to particulates?, Acta Pharm. Sin. B, 13, 2544, 10.1016/j.apsb.2022.10.020 · DOI
  67. Mowat, 2014, Regional specialization within the intestinal immune system, Nat. Rev. Immunol., 14, 667, 10.1038/nri3738 · DOI
  68. Santic, 2006, Francisella tularensis travels a novel, twisted road within macrophages, Trends Microbiol., 14, 37, 10.1016/j.tim.2005.11.008 · DOI
  69. Gilleron, 2013, Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape, Nat. Biotechnol., 31, 638, 10.1038/nbt.2612 · DOI · Paper page
  70. Schultz, 2024, Enhancing RNA encapsulation quantification in lipid nanoparticles: sustainable alternatives to triton X-100 in the RiboGreen assay, Eur. J. Pharm. Biopharm., 205, 10.1016/j.ejpb.2024.114571 · DOI
  71. Matsumoto, 2019, Advanced CUBIC tissue clearing for whole-organ cell profiling, Nat. Protoc., 14, 3506, 10.1038/s41596-019-0240-9 · DOI
  72. Xu, 2024, Tumor microenvironment remodeling-mediated sequential drug delivery potentiates treatment efficacy, Adv. Mater., 36, 10.1002/adma.202312493 · DOI

Cited by

Sorted by citations

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)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review