Mechanism of Protein Corona Formation and Its Application Progress in Nanocarrier Design

Nanoscale targeted delivery systems have gained increasing attention in the field of drug delivery due to their unique physicochemical properties and potential clinical applications. However, once these nanoparticles were systemically administrated, they rapidly adsorb a variety of proteins from the plasma on the surface, forming a complex protein layer known as the "protein corona". The formation of the protein corona is a dynamic and multi-step process. It involves the selective adsorption and desorption of multiple plasma proteins. This process adheres to the "Vroman effect". In such systems, proteins of higher concentration initially binding to the material surface but eventually being replaced by those with higher affinity. Protein adsorption on the nanoparticle surface results in the formation of two layers: inner layer as "hard corona" and outer layer as "soft corona". Proteins in the hard corona bind directly to the nanoparticle surface with high affinity. They form a stable, non-exchangeable layer that confers new biological properties to the nanoparticles. The soft corona consists of proteins that indirectly associate with the nanoparticle surface. These associations occur through interactions with components of the hard corona. The soft corona forms a highly exchangeable layer, dependent on the type of biological fluid.

The composition and structure of the protein corona are impacted by nanoparticle properties, including size, shape, surface charge, and surface chemistry. In vivo environmental factors also impact the corona, such as blood protein concentrations, contact time with proteins and disease microenvironments. The presence of the protein corona significantly alters the biorecognition characteristics of nanoparticles, thereby impacting their in vivo fate, including circulation time, organ and tissue distribution, eventual metabolism and excretion processes. These changes significantly affect the targeting efficiency of nanoparticles as therapeutic agent carriers.

Given the critical role of the protein corona in determining the in vivo fate of nanocarriers, a throughout investigations into its formation mechanisms is essential. Recent researches focusing on elucidating the detailed process of protein corona formation. Studies aim to modulate the composition of the protein corona through the design of specific nanoparticles to optimize the lesion targeting and in vivo fate of drug delivery systems. For instance, designing nanoparticles to selectively adsorb albumin, which is characterized by its biocompatibility and non-immunogenicity, can help reduce recognition and clearance by the reticuloendothelial system, thereby prolonging circulation time. Apolipoproteins can assist nanoparticles in crossing the blood-brain barrier; apolipoprotein B and E can interact with receptors on the surface of cerebral capillary endothelial cells, facilitating endocytosis and promoting transport into the brain. The specific recruitment of complement proteins and other opsonins can achieve selective targeting of particular immune cell populations, control inflammatory responses, and deliver nanovaccines.

Herein, the fundamental principles and impacting factors of protein corona formation on nanoscale delivery systems will be overviewed. Firstly, the morphology of nanoparticles, the surface characteristics of nanoparticles, protein concentrations in the blood, the contact time between nanoparticles and proteins, and the physiological microenvironments all affect the composition and formation process of the protein corona on the nanoparticle surface. Secondly, the specific impacts of the protein corona on the in vivo stability, targeting capability, and immune recognition responses of nanocarriers are discussed. By analyzing practical case studies, the review summarizes the potential application value of the protein corona in enhancing drug delivery efficiency. At last, main challenges including the limitations in protein corona isolation methods, variations in serum sources, and culture conditions are highlighted, which aims to provide a guiding for further explorations in this field. It is believed that with the strengthening of interdisciplinary cooperation and the innovation of technical means, the mysteries of the protein corona will be further revealed, and its potential value will be more widely developed and applied.