Targeting the spleen with nanoparticles could increase the efficacy of vaccines and cancer immunotherapy, and have the potential to treat intracellular infections including leishmaniasis, trypanosome, splenic TB, AIDS, malaria, and hematological disorders. Although, nanoparticle capture in both the liver and spleen has been well documented, there are only a few examples of specific capture in the spleen alone. It is proposed that the larger the nanoparticle size (>400 nm) the greater the specificity and capture within the spleen. Here, we synthesized five nanostructures with different shapes (ranging from spheres, worms, rods, nanorattles, and toroids) and poly(N-isopropylacrylamide), PNIPAM, surface coating using the temperature-directed morphology transformation (TDMT) method. Globular PNIPAM (i.e., water insoluble) surface coatings have been shown to significantly increase cell uptake and enhanced enzyme activity. We incorporated a globular component of PNIPAM on the nanostructure surface and examined the in vivo biodistribution of these nanostructures and accumulation in various tissues and organs in a mouse model. The in vivo biodistribution as a function of time was influenced by the shape and PNIPAM surface composition, in which organ capture and retention was the highest in the spleen. The rods (similar to 150 nm in length and 15 nm in width) showed the highest capture and retention of greater than 35% to the initial injection amount compared to all other nanostructures. It was found that the rods specifically targeted the cells in the red pulp region of the spleen due to the shape and PNIPAM coating of the rod. This remarkable accumulation and selectively into the spleen represents new nanoparticle design parameters to develop new splenotropic effects for vaccines and other therapeutics.