AbstractNanoparticles (NPs) are widely explored for various biomedical applications to make more efficient therapeutics and to develop advanced diagnostic tools. The majority of NP-based systems that have been proven to successfully achieve therapeutic efficacy in vitro did not pass the in vivo conditions because of adverse effects, which have led to systemic toxicity and an unpredicted long-term outcome. Therefore, several NP-based therapeutic systems face challenges for their applicability in clinical trials. These discrepancies in the biological outcome could originate from the binding of proteins on the surface of NPs, thereby achieving a brand new biological identity. It is fundamentally important to understand the so-called “protein corona” around NPs for the development of successful products for therapeutics as well as in other biomedical applications. This review will focus on studies of protein corona formation onto the soft, organic-based NPs, upon incubation in biological media such as human plasma or serum and their physicochemical characteristics. These studies aim to describe these supramolecular structures in relationship with the resultant effects at the interface that might impact the therapeutic efficacy of the designed NPs.