Protease-triggered unveiling of bioactive nanoparticles.

Nanomaterials modified with biological recognition motifs acquire a myriad of functions that can be exploited for the diagnosis and treatment of cancer. Nevertheless, while bioactive domains can be used to target nanoparticles to cell receptors, shuttle them across cell membranes, and activate cell signaling, such modifications typically include cationic or hydrophobic regions that lead to rapid reticuloendothelial system (RES) clearance of particles from the blood, ultimately reducing particle accumulation in tumors. Further functionalization with hydrophilic polymers like poly(ethylene glycol) (PEG) can improve blood half-lives and tumor accumulation, but often at the expense of efficient ligandmediated nanoparticle binding. To address this tradeoff between improved biodistribution and optimal functionality on nanoparticles, we present a general strategy for reversibly veiling bioactive domains on nanoparticles using sterically protective polymers. We demonstrate that these materials effectively accumulate via the hyperpermeable vasculature of tumors and can be activated by cancer-secreted proteases to unveil hidden functional domains. Several cleavable polymers relying on reducible, pHsensitive, and protease-cleavable linkages have been