Fibroblast-Selective Lipid Nanoparticles for Tumor Stromal Transfection

Fibroblasts are abundant and functionally diverse components of the tumor microenvironment and have emerged as attractive targets for stromal modulation in solid tumors. However, selective gene delivery to fibroblasts remains challenging due to their heterogeneity and close spatial association with tumor and immune cells, particularly when using ligand-free lipid nanoparticle (LNP)-based delivery systems. In this study, we applied a selectivity-driven screening approach to identify LNP formulations that preferentially transfect fibroblasts based on lipid composition. Systematic variation of clinically relevant ionizable and helper lipids identified specific LNP compositions that consistently favored fibroblast-selective mRNA expression.