Significance Liver accumulation represents a significant barrier in the development of therapeutically efficacious nanoparticle drug delivery systems. Using a series of lipid nanoparticles with distinct organ-targeting properties, we provide evidence for a plausible mechanism of action for nanoparticle delivery to non-liver tissues. Following intravenous injection, specific proteins in the blood are recruited to the nanoparticle’s surface based on its molecular composition and they endow it with a unique biological identity that governs its ultimate fate in the body. An innovative paradigm emerges from this mechanistic understanding of nanoparticle delivery—endogenous targeting—wherein the molecular composition of a nanoparticle is rationally engineered to interact with specific proteins in the blood to overcome liver accumulation and to target specific organs.