Upon entering the physiological environment, nanoparticles (NPs) are immediately surrounded by a complex and tightly bound layer of biomolecules, or '(hard) protein corona'. The corona controls NP fate in vivo and becomes the interface with cells. One of nanomedicine's central goals is to make NPs capable of active targeting in both imaging and therapy. If the NP is not designed correctly, the resulting corona can cause mistargeting and aberrant biodistribution, unanticipated toxicity, and low therapeutic efficacy. Here we present groundbreaking concepts about nanobio interactions and discuss approaches to bypass protein corona issues and thus enhance the efficacy of NPs. (C) 2016 Elsevier Ltd. All rights reserved.