Endogenous targeting lipid nanoparticles for systemic mRNA delivery to lung cancer tumors.

Systemic delivery of mRNA therapeutics to lung cancer tumors remains challenging despite recent advances in organ-targeting lipid nanoparticles (LNPs). This study introduces novel LNPs, comprising commercially available DC-cholesterol (a cationic derivative of cholesterol) and 113-O12B ionizable lipid (DC_113), which provide selective mRNA translation in healthy lungs while achieving preferential protein expression in pulmonary tumors compared to adjacent lung tissue in an orthotopic cancer model. Analysis of LNPs with diverse ionizable lipids revealed that DC_113 has an apparent pKa above 7.9, the threshold required for efficient interaction with plasma vitronectin (Vtn) and subsequent targeting of Vtn receptors expressed in lung tissue and upregulated in tumors. DC_113 loaded with follistatin (FST)-coded mRNA preferentially delivered therapeutic cargo to tumors, resulting in significant FST expression and subsequent inhibition of Activin A, a key driver of cancer progression and cachexia. This cancer-preferential mRNA delivery achieved approximately 2.5-fold greater reduction in tumor burden than liver-tropic LNPs producing systemic FST. Furthermore, it efficiently mitigated cancer cachexia by improving food intake, maintaining body weight, and preserving muscle and adipose tissues without adverse effects. These findings present a novel strategy for endogenous targeting of LNPs to lung tumors that can enhance the potential of mRNA-based interventions for pulmonary cancer.