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Fibroblast-Selective Lipid Nanoparticles for Tumor Stromal Transfection.

Na Yeon Kim1, Yeon Hui Yang1, Takatsugu Ishimoto2

  • 1Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.

Molecular Pharmaceutics
|July 16, 2026
PubMed
Summary

Researchers identified specific lipid nanoparticle (LNP) compositions for targeted gene delivery to fibroblasts. This breakthrough enhances fibroblast-selective mRNA expression in tumor microenvironments, aiding stromal modulation strategies.

Keywords:
fibroblast selectivityligand-free deliverylipid nanoparticlemRNA deliverytumor microenvironment

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Area of Science:

  • Biomedical Engineering
  • Molecular Biology
  • Cancer Research

Background:

  • Fibroblasts are key components of the tumor microenvironment, offering potential therapeutic targets.
  • Selective gene delivery to fibroblasts is difficult due to their heterogeneity and proximity to tumor and immune cells.
  • Ligand-free lipid nanoparticle (LNP) systems face challenges in achieving fibroblast selectivity.

Purpose of the Study:

  • To identify LNP formulations that preferentially transfect fibroblasts.
  • To determine the role of lipid composition in achieving fibroblast selectivity.
  • To evaluate the efficacy of fibroblast-selective LNPs in vitro and in vivo.

Main Methods:

  • A selectivity-driven screening approach was used to identify fibroblast-targeting LNPs.
  • Systematic variation of ionizable and helper lipids in LNP formulations.
  • In vitro, co-culture, and peritumoral in vivo models were employed to assess LNP performance.

Main Results:

  • Specific LNP lipid compositions consistently favored fibroblast-selective mRNA expression.
  • Preferential transgene expression in fibroblasts was observed in vitro and maintained in co-culture models.
  • Peritumoral administration of optimized LNPs in mice showed preferential mRNA expression in tumor-associated stromal fibroblasts.

Conclusions:

  • LNP lipid composition is a critical factor in achieving fibroblast-selective mRNA expression.
  • The findings support the development of targeted LNP-based therapies for fibroblast modulation in solid tumors.
  • This study provides a foundation for engineering LNPs for precise delivery to tumor-associated fibroblasts.