Inorganic nanoparticles are frequently engineered with an organic surface coating to improve their physicochemical properties, and it is well known that their colloidal properties(1) may change upon internalization by cells(2,3). While the stability of such nanoparticles is typically assayed in simple in vitro tests, their stability in a mammalian organism remains unknown. Here, we show that firmly grafted polymer shells around gold nanoparticles may degrade when injected into rats. We synthesized monodisperse radioactively labelled gold nanoparticles (Au-198)(4) and engineered an In-111-labelled polymer shell around them(5). Upon intravenous injection into rats, quantitative biodistribution analyses performed independently for Au-198 and In-111 showed partial removal of the polymer shell in vivo. While Au-198 accumulates mostly in the liver, part of the In-111 shows a non-particulate biodistribution similar to intravenous injection of chelated In-111. Further in vitro studies suggest that degradation of the polymer shell is caused by proteolytic enzymes in the liver. Our results show that even nanoparticles with high colloidal stability can change their physicochemical properties in vivo.