Quantitative Analysis of Protein Corona on Precoated Protein Nanoparticles and Determined Nanoparticles with Ultralow Protein Corona and Efficient Targeting in Vivo

Abstract

The protein corona on nanoparticles (NPs) is a critical problem that often screens the targeting molecules and becomes one of the key reasons for the lack of practical application in nanotherapy. It is critical to fully understand the mechanism of the nanoparticle–biological interactions to design the nanoparticle-based therapeutic agents. Some types of proteins can be precoated on the nanoparticles to avoid unwanted protein attachment; however, the ultralow level of protein corona is hard to achieve, and the relationship of the antifouling property of the precoated protein nanoparticles with protein conformation and protein–nanoparticle interaction energy has never been investigated. In this work, we provided the quantitative protein corona composition analysis on different precoated protein nanoparticles, and on the basis of the molecular simulation process, we found their antifouling property strongly depended on the interaction energy of the precoated protein–serum protein pair and the number of hydrogen bonds formed between them. Furthermore, it also depended on the nanoparticle–serum protein pair interaction energy and the protein conformation on the nanoparticle. The casein coated nanoparticle with the antifouling property was determined, and after aptamer conjugation and drug loading, they exhibited superior targeting and internalization behavior for photodynamic and photothermal therapy in vitro and in vivo. Our work adds to the understanding of the protein corona behavior of precoated protein nanoparticles, and the determined antifouling NP can potentially be used as a highly efficient nanodrug carrier.

Chemical and Biophysical Signatures of the Protein Corona in Nanomedicine

“…For instance, Zhong et al synthesized nanoparticles with precoated proteins by applying 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide/ N-hydroxysuccinimide (EDC/NHS) chemistry between the exposed carboxylic groups of the starch-coated poly(methyl methacrylate-co-acrylic acid) nanoparticles (St NPs) and the primary amino groups of various proteins. 25 The antifouling behavior of the St NPs was found to be strongly dependent on the interaction energy between the precoated protein and serum protein pair. The minimal corona formation observed in casein-precoated St NPs was attributed to the highest interaction energy and minimal hydrogen-bonding formation.…”

“…Numerous studies have exploited surface-modification chemistries to elucidate the mechanisms of protein–protein and nanomaterial–protein interactions. For instance, Zhong et al synthesized nanoparticles with precoated proteins by applying 1-ethyl-3-(3-(dimethylamino)­propyl)-carbodiimide/ N -hydroxysuccinimide (EDC/NHS) chemistry between the exposed carboxylic groups of the starch-coated poly­(methyl methacrylate- co -acrylic acid) nanoparticles (St NPs) and the primary amino groups of various proteins . The antifouling behavior of the St NPs was found to be strongly dependent on the interaction energy between the precoated protein and serum protein pair.…”

Effect of Albumin Corona Conformation on In Vitro and In Vivo Profiles of Intravenously Administered Nanoparticles

“…In recent decades, nanoparticles (NPs) have gained significant attention as a versatile tool for drug delivery and disease diagnosis. , However, the inconsistent results observed in vitro and in vivo have posed significant challenges for translational studies, mainly due to the complex fate of NPs in vivo . , NPs tend to nonspecifically adsorb proteins in biological fluids, leading to the formation of a protein corona (PC), which can significantly affect their biological behavior and therapeutic efficacy. − PC may endow NPs brand new physical and chemical properties causing diverse biological reactions in the body . For instance, when exposed to plasma proteins, NPs typically develop a PC that can increase the particle size by 20–40 nm .…”

Design of a nanocomposite with gold nanoparticles as the core and casein-templated gold nanoclusters as the shell with ultra-low protein corona for enhanced photodynamic therapy

“…18 In addition, we previously demonstrated that the casein coated nanoparticle has an excellent antifouling property (ultra-low protein corona) due to the high interaction energy of the casein–serum protein pair and the small number of hydrogen bond formations between them. 19 The antifouling properties of nanoparticles will avoid the deposition of complement proteins on the surfaces, which could avoid inducing strong complement activation and extend the blood circulation time. 20…”

“…18 In addition, we previously demonstrated that the casein coated nanoparticle has an excellent antifouling property (ultra-low protein corona) due to the high interaction energy of the casein-serum protein pair and the small number of hydrogen bond formations between them. 19 The antifouling properties of nanoparticles will avoid the deposition of complement proteins on the surfaces, which could avoid inducing strong complement activation and extend the blood circulation time. 20 Although the ultrasmall AuNCs have many advantages for biological applications, the enthalpic limit for a spherical nanoparticle occurs at a size of about 30 nm, indicating that nanoparticles smaller than this limit will not be able to drive the membrane-wrapping process effectively.…”