Targeted delivery of therapeutic agents to tumor sites increases efficacy and limits off-target toxicity. Nanoparticles are an emerging class of targeted drug delivery systems. Commonly, nanoparticles are coated with poly(ethylene glycol) (PEG) to reduce off-target uptake by cells of the mononuclear phagocyte system (MPS) and a targeting moiety to promote uptake at the desired location. This approach holds great promise, but such constructs still predominantly accumulate in the liver. Here we demonstrate a different approach to tumor targeting using nanoparticles functionalized with a PEG coating that is shed in the presence of matrix metalloproteinase-2 (MMP-2), which is overexpressed in many tumor microenvironments. There was very little uptake of intact particles by human breast adenocarcinoma cells, whereas, when the same cells were treated with particles in the presence of MMP-2, the resulting denuded particles were rapidly taken up by the cells. This system is remarkably simple as the core nanoparticles revealed by PEG cleavage are not modified; uptake is driven simply by revealing the nanoparticle surface. The cleavable linker is a modular component that, in the future, can be designed to respond to other stimuli. This approach could lead to improved imaging and targeted drug delivery for solid tumors.