Perspectives on Protein-Nanoparticle Interactions at the In Vivo Level.

The distinct features of nanoparticles have provided a vast opportunity of developing new diagnosis and therapy strategies for miscellaneous diseases. Although a few nanomedicines are available in the market or in the translation stage, many important issues are still unsolved. When entering the body, nanomaterials will be quickly coated by proteins from their surroundings, forming a corona on their surface, the so-called protein corona. Studies have shown that the protein corona has many important biological implications, particularly at the in vivo level. For example, they can promote the immune system to rapidly clear these outer materials and prevent nanoparticles from playing their designed role in therapy. In this Perspective, the available techniques for characterizing protein-nanoparticle interactions are critically summarized. Effects of nanoparticle properties and environmental factors on protein corona formation, which can further regulate the in vivo fate of nanoparticles, are highlighted and discussed. Moreover, recent progress on the biomedical application of protein corona-engineered nanoparticles is introduced, and future directions for this important yet challenging research area are also briefly discussed.

Protein Corona-Mediated Inhibition of Nanozyme Activity: Impact of Protein Shape.

During biomedical applications, nanozymes, exhibiting enzyme-like characteristics, inevitably come into contact with biological fluids in living systems, leading to the formation of a protein corona on their surface. Although it is acknowledged that molecular adsorption can influence the catalytic activity of nanozymes, there is a dearth of understanding regarding the impact of the protein corona on nanozyme activity and its determinant factors. In order to address this gap, we employed the AuNR@Pt@PDDAC [PDDAC, poly(diallyldimethylammonium chloride)] nanorod (NR) as a model nanozyme with multiple activities, including peroxidase, oxidase, and catalase-mimetic activities, to investigate the inhibitory effects of the protein corona on the catalytic activity. After the identification of major components in the plasma protein corona on the NR, we observed that spherical proteins and fibrous proteins induced distinct inhibitory effects on the catalytic activity of nanozymes. To elucidate the underlying mechanism, we uncovered that the adsorbed proteins assembled on the surface of the nanozymes, forming protein networks (PNs). Notably, the PNs derived from fibrous proteins exhibited a screen mesh-like structure with smaller pore sizes compared to those formed by spherical proteins. This structural disparity resulted in a reduced efficiency for the permeation of substrate molecules, leading to a more robust inhibition in activity. These findings underscore the significance of the protein shape as a crucial factor influencing nanozyme activity. This revelation provides valuable insights for the rational design and application of nanozymes in the biomedical fields.

Molecular Serum Albumin Unmask Nanobio Properties of Molecular Graphenes in Shungite Carbon Nanoparticles.

Serum albumin is a popular macromolecule for studying the effect of proteins on the colloidal stability of nanoparticle (NP) dispersions, as well as the protein-nanoparticle interaction and protein corona formation. In this work, we analyze the specific conformation-dependent phase, redox, and fatty acid delivery properties of bovine albumin in the presence of shungite carbon (ShC) molecular graphenes stabilized in aqueous dispersions in the form of NPs in order to reveal the features of NP bioactivity. The formation of NP complexes with proteins (protein corona around NP) affects the transport properties of albumin for the delivery of fatty acids. Being acceptors of electrons and ligands, ShC NPs are capable of exhibiting both their own biological activity and significantly affecting conformational and phase transformations in protein systems.

Molecular insights into nanoplastics-peptides binding and their interactions with the lipid membrane.

Micro- and nanoplastics have become a significant concern, due to their ubiquitous presence in the environment. These particles can be internalized by the human body through ingestion, inhalation, or dermal contact, and then they can interact with environmental or biological molecules, such as proteins, resulting in the formation of the protein corona. However, information on the role of protein corona in the human body is still missing. Coarse-grain models of the nanoplastics and pentapeptides were created and simulated at the microscale to study the role of protein corona. Additionally, a lipid bilayer coarse-grain model was reproduced to investigate the behavior of the coronated nanoplastics in proximity of a lipid bilayer. Hydrophobic and aromatic amino acids have a high tendency to create stable bonds with all nanoplastics. Moreover, polystyrene and polypropylene establish bonds with polar and charged amino acids. When the coronated nanoplastics are close to a lipid bilayer, different behaviors can be observed. Polyethylene creates a single polymeric chain, while polypropylene tends to break down into its single chains. Polystyrene can both separate into its individual chains and remain aggregated. The protein corona plays an important role when interacting with the nanoplastics and the lipid membrane. More studies are needed to validate the results and to enhance the complexity of the systems.

Probing Protein Corona Formation around Gold Nanoparticles: Effects of Surface Coating.

There has been much interest in integrating various inorganic nanoparticles (nanoscale colloids) in biology and medicine. However, buildup of a protein corona around the nanoparticles in biological media, driven by nonspecific interactions, remains a major hurdle for the translation of nanomedicine into clinical applications. In this study, we investigate the interactions between gold nanoparticles and serum proteins using a series of dihydrolipoic acid (DHLA)-based ligands. We employed gel electrophoresis combined with UV-vis absorption and dynamic light scattering to correlate protein adsorption with the nature and size of the ligand used. For instance, we found that AuNPs capped with DHLA alone promote nonspecific protein adsorption. In comparison, capping AuNPs with polyethylene glycol- or zwitterion-appended DHLA essentially prevents corona formation, regardless of ligand charge and size. Our results highlight the crucial role of surface chemistry and core material in protein corona formation and offer valuable information for the design of colloidal nanomaterials for biological applications.

Unraveling Intracellular Protein Corona Components of Nanoplastics via Photocatalytic Protein Proximity Labeling.

Bioaccumulation of nanoplastic particles has drawn increasing attention regarding environmental sustainability and biosafety. How nanoplastic particles interact with the cellular milieu still remains elusive. Herein, we exemplify a general approach to profile the composition of a "protein corona" interacting with nanoparticles via the photocatalytic protein proximity labeling method. To enable photocatalytic proximity labeling of the proteome interacting with particles, iodine-substituted BODIPY (I-BODIPY) is selected as the photosensitizer and covalently conjugated onto amino-polystyrene nanoparticles as a model system. Next, selective proximity labeling of interacting proteins is demonstrated using I-BODIPY-labeled nanoplastic particles in both Escherichia coli lysate and live alpha mouse liver 12 cells. Mechanistic studies reveal that the covalent modifications of proteins by an aminoalkyne substrate are conducted via a reactive oxygen species photosensitization pathway. Further proteomic analysis uncovers that mitochondria-related proteins are intensively involved in the protein corona, indicating substantial interactions between nanoplastic particles and mitochondria. In addition, proteostasis network components are also identified, accompanied by consequent cellular proteome aggregation confirmed by fluorescence imaging. Together, this work exemplifies a general strategy to interrogate the composition of the protein corona of nanomaterials by endowing them with photooxidation properties to enable photocatalytic protein proximity labeling function.

Unveiling the challenges of engineered protein corona from the proteins' perspective.

It is well known that protein corona affects the "biological identity" of nanoparticles (NPs), which has been seen as both a challenge and an opportunity. Approaches have moved from avoiding protein adsorption to trying to direct it, taking advantage of the formation of a protein corona to favorably modify the pharmacokinetic parameters of NPs. Although promising, the results obtained with engineered NPs still need to be completely understood. While much effort has been put into understanding how the surface of nanomaterials affects protein absorption, less is known about how proteins can affect corona formation due to their specific physicochemical properties. This review addresses this knowledge gap, examining key protein factors influencing corona formation, highlighting current challenges in studying protein-protein interactions, and discussing future perspectives in the field.

The in vitro gastrointestinal digestion-associated protein corona of polystyrene nano- and microplastics increases their uptake by human THP-1-derived macrophages.

BACKGROUND: Micro- and nanoplastics (MNPs) represent one of the most widespread environmental pollutants of the twenty-first century to which all humans are orally exposed. Upon ingestion, MNPs pass harsh biochemical conditions within the gastrointestinal tract, causing a unique protein corona on the MNP surface. Little is known about the digestion-associated protein corona and its impact on the cellular uptake of MNPs. Here, we systematically studied the influence of gastrointestinal digestion on the cellular uptake of neutral and charged polystyrene MNPs using THP-1-derived macrophages. RESULTS: The protein corona composition was quantified using LC‒MS-MS-based proteomics, and the cellular uptake of MNPs was determined using flow cytometry and confocal microscopy. Gastrointestinal digestion resulted in a distinct protein corona on MNPs that was retained in serum-containing cell culture medium. Digestion increased the uptake of uncharged MNPs below 500 nm by 4.0-6.1-fold but did not affect the uptake of larger sized or charged MNPs. Forty proteins showed a good correlation between protein abundance and MNP uptake, including coagulation factors, apolipoproteins and vitronectin. CONCLUSION: This study provides quantitative data on the presence of gastrointestinal proteins on MNPs and relates this to cellular uptake, underpinning the need to include the protein corona in hazard assessment of MNPs.

Fe3O4SPIONs in cancer theranostics-structure versus interactions with proteins and methods of their investigation.

As the second leading cause of death worldwide, neoplastic diseases are one of the biggest challenges for public health care. Contemporary medicine seeks potential tools for fighting cancer within nanomedicine, as various nanomaterials can be used for both diagnostics and therapies. Among those of particular interest are superparamagnetic iron oxide nanoparticles (SPIONs), due to their unique magnetic properties,. However, while the number of new SPIONs, suitably modified and functionalized, designed for medical purposes, has been gradually increasing, it has not yet been translated into the number of approved clinical solutions. The presented review covers various issues related to SPIONs of potential theranostic applications. It refers to structural considerations (the nanoparticle core, most often used modifications and functionalizations) and the ways of characterizing newly designed nanoparticles. The discussion about the phenomenon of protein corona formation leads to the conclusion that the scarcity of proper tools to investigate the interactions between SPIONs and human serum proteins is the reason for difficulties in introducing them into clinical applications. The review emphasizes the importance of understanding the mechanism behind the protein corona formation, as it has a crucial impact on the effectiveness of designed SPIONs in the physiological environment.

Regulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery.

The dynamic protein corona formed on nanocarriers has been revealed to strongly affect their in vivo behaviors. Precisely manipulating the formation of protein corona on nanocarriers may provide an alternative impetus for specific drug delivery. Herein, we explore the role of glycosylated polyhydroxy polymer-modified nanovesicles (CP-LVs) with different amino/hydroxyl ratios in protein corona formation and evolution. CP-LVs with an amino/hydroxyl ratio of approximately 0.4 (CP1-LVs) are found to efficiently suppress immunoglobulin adsorption in blood and livers, resulting in prolonged circulation. Moreover, CP1-LVs adsorb abundant tumor distinctive proteins, such as CD44 and osteopontin in tumor interstitial fluids, mediating selective tumor cell internalization. The proteins corona transformation specific to the environment appears to be affected by the electrostatic interaction between CP-LVs and proteins with diverse isoelectric points. Benefiting from surface modification-mediated protein corona regulation, paclitaxel-loaded CP1-LVs demonstrate superior antitumor efficacy to PEGylated liposomes. Our work offers a perspective on rational surface-design of nanocarriers to modulate the protein corona formation for efficient drug delivery.

Protein Coronas Derived from Mucus Act as Both Spear and Shield to Regulate Transferrin Functionalized Nanoparticle Transcellular Transport in Enterocytes.

The epithelial mucosa is a key biological barrier faced by gastrointestinal, intraoral, intranasal, ocular, and vaginal drug delivery. Ligand-modified nanoparticles demonstrate excellent ability on this process, but their efficacy is diminished by the formation of protein coronas (PCs) when they interact with biological matrices. PCs are broadly implicated in affecting the fate of NPs in vivo and in vitro, yet few studies have investigated PCs formed during interactions of NPs with the epithelial mucosa, especially mucus. In this study, we constructed transferrin modified NPs (Tf-NPs) as a model and explored the mechanisms and effects that epithelial mucosa had on PCs formation and the subsequent impact on the transcellular transport of Tf-NPs. In mucus-secreting cells, Tf-NPs adsorbed more proteins from the mucus layers, which masked, displaced, and dampened the active targeting effects of Tf-NPs, thereby weakening endocytosis and transcellular transport efficiencies. In mucus-free cells, Tf-NPs adsorbed more proteins during intracellular trafficking, which enhanced transcytosis related functions. Inspired by soft coronas and artificial biomimetic membranes, we used mucin as an "active PC" to precoat Tf-NPs (M@Tf-NPs), which limited the negative impacts of "passive PCs" formed during interface with the epithelial mucosa and improved favorable routes of endocytosis. M@Tf-NPs adsorbed more proteins associated with endoplasmic reticulum-Golgi functions, prompting enhanced intracellular transport and exocytosis. In summary, mucus shielded against the absorption of Tf-NPs, but also could be employed as a spear to break through the epithelial mucosa barrier. These findings offer a theoretical foundation and design platform to enhance the efficiency of oral-administered nanomedicines.

Unveiling the effects of protein corona formation on the aggregation kinetics of gold nanoparticles in monovalent and divalent electrolytes.

Elucidation of the aggregation behaviors of gold nanoparticles (AuNPs) in water systems is crucial to understanding their environmental fate and transport as well as human health effects. We investigated the early-stage aggregation kinetics of AuNPs coated by human serum albumin (HSA) protein corona (PC) in NaCl and CaCl2 through time-resolved dynamic light scattering. We found that the aggregation of PC-AuNPs depended on the concerted effects of electrolyte concentration, valence, and HSA concentration. At low HSA concentration (≤0.005 g/L), the aggregation kinetics of PC-AuNPs was similar to that of bare AuNPs due to insignificant HSA adsorption. At intermediate HSA concentrations of 0.025-0.050 g/L, the aggregation of PC-AuNPs was retarded in both electrolytes due to steric repulsive forces imparted by the PCs. Additionally, HSA PCs had a weaker retardation effect on PC-AuNPs aggregation in divalent than in monovalent electrolytes. Quartz crystal microbalance measurements revealed that the presence of Ca2+ promoted additional HSA adsorption on PC-AuNPs likely via -COO-Ca2+ bond, and eventually enhanced the aggregation between PC-AuNPs. High-concentration HSA (>0.5 g/L) resulted in no PC-AuNPs aggregation regardless of electrolyte valence and concentrations. Finally, desorption of HSA barely occurred after adsorption on the gold surface, suggesting that the formation of PC-AuNPs is mostly irreversible.

Overcoming colloidal nanoparticle aggregation in biological milieu for cancer therapeutic delivery: Perspectives of materials and particle design.

Nanoparticles as cancer therapeutic carrier fail in clinical translation due to complex biological environments in vivo consisting of electrolytes and proteins which render nanoparticle aggregation and unable to reach action site. This review identifies the desirable characteristics of nanoparticles and their constituent materials that prevent aggregation from site of administration (oral, lung, injection) to target site. Oral nanoparticles should ideally be 75-100 nm whereas the size of pulmonary nanoparticles minimally affects their aggregation. Nanoparticles generally should carry excess negative surface charges particularly in fasting state and exert steric hindrance through surface decoration with citrate, anionic surfactants and large polymeric chains (polyethylene glycol and polyvinylpyrrolidone) to prevent aggregation. Anionic as well as cationic nanoparticles are both predisposed to protein corona formation as a function of biological protein isoelectric points. Their nanoparticulate surface composition as such should confer hydrophilicity or steric hindrance to evade protein corona formation or its formation should translate into steric hindrance or surface negative charges to prevent further aggregation. Unexpectedly, smaller and cationic nanoparticles are less prone to aggregation at cancer cell interface favoring endocytosis whereas aggregation is essential to enable nanoparticles retention and subsequent cancer cell uptake in tumor microenvironment. Present studies are largely conducted in vitro with simplified simulated biological media. Future aggregation assessment of nanoparticles in biological fluids that mimic that of patients is imperative to address conflicting materials and designs required as a function of body sites in order to realize the future clinical benefits.

Effect of Lipid Corona on Phenylalanine-Functionalized Gold Nanoparticles to Develop Stable and Corona-Free Systems.

Conventional gold nanoparticles (Au NPs) have many limitations, such as aggregation and subsequent precipitation in the medium of high ionic strength and protein molecules. Furthermore, when exposed to biological fluids, nanoparticles form a protein corona, which controls different biological processes such as the circulation lifetime, drug release profile, biodistribution, and in vivo cellular distribution. These limitations reduce the functionality of Au NPs in targeted delivery, bioimaging, gene delivery, drug delivery, and other biomedical applications. To circumvent these problems, there are numerous attempts to design corona-free and stable nanoparticles. Here, we report for the first time that lipid corona (coating of lipid) formation on phenylalanine-functionalized Au NPs (AuPhe NPs) imparts excellent stability against the high ionic strength of bivalent metal ions, amino acids, and proteins of different charges as compared to bare nanoparticles. Moreover, this work is focused on the ability of lipid corona formation on AuPhe NPs to prevent protein adsorption in the presence of cell culture medium (CCM), oppositely charged protein (e.g., histone 3), and human serum albumin (HSA). The results demonstrate that the lipid corona successfully protects the AuPhe NPs from protein adsorption, leading to the development of corona-free character. This unique achievement has profound implications for enhancing the biomedical utility and safety of these nanoparticles.

Impact of Whey Protein Corona Formation around TiO2 Nanoparticles on Their Physiochemical Properties and Gastrointestinal Fate.

Previously, we found that whey proteins form biomolecular coronas around titanium dioxide (TiO2) nanoparticles. Here, the gastrointestinal fate of whey protein-coated TiO2 nanoparticles and their interactions with gut microbiota were investigated. The antioxidant activity of protein-coated nanoparticles was enhanced after simulated digestion. The structure of the whey proteins was changed after they adsorbed to the surfaces of the TiO2 nanoparticles, which reduced their hydrolysis under simulated gastrointestinal conditions. The presence of protein coronas also regulated the impact of the TiO2 nanoparticles on colonic fermentation, including promoting the production of short-chain fatty acids. Bare TiO2 nanoparticles significantly increased the proportion of harmful bacteria and decreased the proportion of beneficial bacteria, but the presence of protein coronas alleviated this effect. In particular, the proportion of beneficial bacteria, such as Bacteroides and Bifidobacterium, was enhanced for the coated nanoparticles. Our results suggest that the formation of a whey protein corona around TiO2 nanoparticles may have beneficial effects on their behavior within the colon. This study provides valuable new insights into the potential impact of protein coronas on the gastrointestinal fate of inorganic nanoparticles.

Lipid-mediated protein corona regulation with increased apolipoprotein A-I recruitment for glioma targeting.

Protein corona has long been a source of concern, as it might impair the targeting efficacy of targeted drug delivery systems. However, engineered up-regulating the adsorption of certain functional serum proteins could provide nanoparticles with specific targeting drug delivery capacity. Herein, apolipoprotein A-I absorption increased nanoparticles (SPC-PLGA NPs), composed with the Food and Drug Administration approved intravenously injectable soybean phosphatidylcholine (SPC) and poly (DL-lactide-co-glycolide) (PLGA), were fabricated for enhanced glioma targeting. Due to the high affinity of SPC and apolipoprotein A-I, the percentage of apolipoprotein A-I in the protein corona of SPC-PLGA NPs was 2.19-fold higher than that of nanoparticles without SPC, which made SPC-PLGA NPs have superior glioma targeting ability through binding to scavenger receptor class BI on blood-brain barrier and glioma cells both in vitro and in vivo. SPC-PLGA NPs loaded with paclitaxel could effectively reduce glioma invasion and prolong the survival time of glioma-bearing mice. In conclusion, we provided a good example of the direction of achieving targeting drug delivery based on protein corona regulation.

A platform for microplastic assessment in aquatic environments based on the protein corona-induced aggregation effect.

The environmental hazards of microplastics have received widespread attention. However, the in-situ detection of microplastics, particularly in aquatic environments, has been challenged by the limitations of detection methods, the large-scale instruments, and small size. Herein, a photoelectrochemical sensor based on the protein corona-induced aggregation effect is designed for the detection of polystyrene microplastics. The sensor has advantages of high sensitivity, reproducibility, and detection capability. A linear detection range of 0.5-500 µg mL-1, a method detection limit of 0.06 µg mL-1, and a limit of quantification of 0.14 µg mL-1 are achieved. Furthermore, the relative standard deviations of intra-day and inter-day precision, ranging from 0.56% to 4.63% and 0.84%-3.36% are obtained. A digital multimeter was employed to construct a platform for the real-time detection in real water samples, streamlining the detection process and yielding clear results. We believe this sensor provides new insight for the in-situ real-time detection of microplastics and has broad applications for the analysis of microplastic pollution in aquatic environments.

Development of a fast and simple method for the isolation of superparamagnetic iron oxide nanoparticles protein corona from protein-rich matrices.

The adsorption of proteins onto the surface of nanoparticle (NP) leads to the formation of the so-called "protein corona" as consisting both loosely and tightly bound proteins. It is well established that the biological identity of NPs that may be acquired after exposure to a biological matrix is mostly provided by the components of the hard corona as the pristine surface is generally less accessible for binding. For that reason, the isolation and the characterisation of the NP-corona complexes and identification of the associated biomolecules can help in understanding its biological behaviour. Established methods for the isolation of the NP-HC complexes are time-demanding and can lead to different results based on the isolation method applied. Herein, we have developed a fast and simple method using ferromagnetic beads isolated from commercial MACS column and used for the isolation of superparamagnetic NP following exposure to different types of biological milieu. We first demonstrated the ability to easily isolate superparamagnetic iron oxide NPs (IONPs) from different concentrations of human blood plasma, and also tested the method on the corona isolation using more complex biological matrices, such as culture medium containing pulmonary mucus where the ordinary corona methods cannot be applied. Our developed method showed less than 20% difference in plasma corona composition when compared with centrifugation. It also showed effective isolation of NP-HC complexes from mucus-containing culture media upon comparing with centrifugation and MACS columns, which failed to wash out the unbound proteins. Our study was supported with a full characterisation profile including dynamic light scattering, nanoparticle tracking analysis, analytical disk centrifuge, and zeta potentials. The biomolecules/ proteins composing the HC were separated by vertical gel electrophoresis and subsequently analysed by liquid chromatography-tandem mass spectrometry. In addition to our achievements in comparing different isolation methods to separate IONPs with corona from human plasma, this is the first study that provides a complete characterisation profile of particle protein corona after exposure in vitro to pulmonary mucus-containing culture media.

Separation of protein corona from nanoparticles under intracellular acidic conditions: effect of protonation on nanoparticle-protein and protein-protein interactions.

Protein coronas separate from nanoparticles under intracellular acidic conditions however, competitive adsorption of multiple proteins and their protein network formation under different pH conditions have not yet been systematically studied at the atomic scale. Herein, we report all-atom molecular dynamics simulations of plasma proteins (human serum albumin and immunoglobulin gamma-1 chain C) adsorbed to 10 nm-sized carboxyl-terminated polystyrene (PS) nanoparticles at different protonation states that mimic extracellular and intracellular pH conditions of 7, 6-5, and 4.5. Binding free energies are calculated from umbrella sampling simulations, showing the significantly weakened binding between PS particles and proteins at the protonation state at pH 4.5, in agreement with experiments showing the separation of protein corona from nanoparticles at pH 4.5. Mixtures of multiple proteins and PS particles are also simulated, showing much less protein adsorption and protein cluster formation at the protonation state at pH 4.5 than that at higher pH values, which are further confirmed by calculating the diffusivities and hydrodynamic radii of individual proteins. In particular, electrostatic particle-protein and protein-protein interactions are significantly weakened by a combination of particle and protein protonation rather than by particle protonation alone, to an extent dependent on different proteins. These findings help explain the experimental observations regarding separation of protein corona from nanoparticles under intracellular acidic conditions at pH 4.5 but not at higher pH, supporting that acidification cannot be the only reason for this separation during the process of endosome maturation.

Protein corona exacerbated inflammatory response in macrophages elicited by CdTe quantum dots.

Nano-bio interface is significant concern in nanomedicine. When nanoparticles (NPs) come into contact with cells, they form complexes with proteins known as protein corona (PC). Cadmium telluride quantum dots (CdTe QDs) have been applied as bioimaging probes and for macrophage theragnostic. However, the impact of protein corona on the behavior of CdTe QDs is not well understood. Macrophages play a crucial role in defending against NPs. In this study, RAW264.7 cells were used to investigated the inflammatory response in macrophages when exposed to CdTe QDs before and after PC formation in fetal bovine serum. The results indicated that protein corona polarized more macrophages towards M1 phenotype. Transcriptomics analysis revealed that PC-CdTe QDs altered a greater number of differentially expressed genes (DEGs) compared to CdTe QDs (177 and 398) at 1.0 µM in macrophages. The DEGs affected by PC-CdTe QDs contained several personalized inflammatory cytokines. The enriched pathways after PC formation included Cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and TNF signaling pathway, etc. Furthermore, PC specifically exacerbated the overexpression of CCL2 and IL-1ß proteins. Importantly, PC altered the mechanism of CdTe QD-induced pyroptosis, shifting it from activating NLRC4 to both NLRP1 and NLRP3 inflammasomes, and from cleaving GSDMD and GSDMB to GSDMB alone. Overall, protein corona exacerbated the inflammatory response induced by CdTe QDs in macrophages. This study provides valuable insight into the pro-inflammatory effect of protein corona on CdTe QDs, with implications for their use in bioimaging or macrophage theragnostic by either exploiting or eliminating this biological interface effect.