Lung cancer is the leading cause of mortality in the US affecting 160,000 patients yearly with a five-year survival of 17%. The majority of lung cancers harbor KRAS mutations that over-activate the RAS protein in the RAS-MAPK signaling pathway, RAS-RAF-MEK-ERK, leading to increased pathway activity, cell division, and tumor growth. Unfortunately, due to its protein structure, RAS is difficult to drug with kinase inhibitors because it has no accessible binding pocket. Instead, therapies inhibiting kinases downstream of the RAS-MAPK pathway, such as the MEK inhibitor trametinib, have shown to be effective in vitro. However, trametinib tends to have toxic side effects from systemic application that leads to dose alterations and diminishes its use as a viable therapy. We recently developed a novel nanomedicine platform to package kinase inhibitors with high drug loading. We have found that the nanoparticles are taken up by caveolin-mediated endocytosis across lung endothelium to increase the local concentration of trametinib at the tumor site, treating primary and localized metastases and reducing systemic exposure of trametinib in non-cancerous tissues. Notably, this caveolin-mediated uptake of trametinib nanoparticles alters the systemic biodistribution. Thus, the selective targeting decreases the toxicity of systemic kinase inhibitor exposure to concomitantly improve the therapeutic index and efficacy.