Nanoparticle (NP)-based therapeutics have ushered in a new era in translational medicine. However, despite the clinical success of NP technology, it is not well-understood how NPs fundamentally change in biological environments. When introduced into physiological fluids, NPs are coated by proteins, forming a protein corona (PC). The PC has the potential to endow NPs with a new identity and alter their bioactivity, stability, and destination. Additionally, the conformation of proteins is sensitive to their physical and chemical surroundings. Therefore, biological factors and protein-NP-interactions can induce changes in the conformation and orientation of proteins in vivo. Since the function of a protein is closely connected to its folded structure, slight differences in the surrounding environment as well as the surface characteristics of the NP materials may cause proteins to lose or gain a function. As a result, this can alter the downstream functionality of the NPs. This review introduces the main biological factors affecting the conformation of proteins associated with the PC. Then, four types of NPs with extensive utility in biomedical applications are described in greater detail, focusing on the conformation and orientation of adsorbed proteins. This is followed by a discussion on the instances in which the conformation of adsorbed proteins can be leveraged for therapeutic purposes, such as controlling protein conformation in assembled matrices in tissue, as well as controlling the PC conformation for modulating immune responses. The review concludes with a perspective on the remaining challenges and unexplored areas at the interface of PC and NP research.