Endogenous Targeting of Lipid Nanoparticles to Kidney Tumors

Although the delivery of genetic therapies to tumors using nanoparticles remains challenging, targeting may be enabled via plasma membrane receptors overexpressed on certain cancer cells. Here, we developed an endogenous targeting strategy for trafficking intravenously administered mRNA (and siRNA) lipid nanoparticles (LNPs) to clear cell renal cell carcinoma (ccRCC) kidney tumors. LNPs were engineered to adsorb circulating plasma vitronectin (Vtn), the ligand for α_Vβ₃ integrin/vitronectin receptor (Vtn-R), which is overexpressed in ccRCC. Functional mRNA delivery to human ccRCC cells was enhanced 952-fold <i>in vitro</i> and 42-fold in patient-derived ccRCC tumor fragments orthotopically transplanted in mice. This proof-of-concept study represents a new direction in the cancer nanomedicine field by modulating the physicochemical properties of LNPs to achieve <i>in situ</i> ligand binding and tumor targeting.