A phosphatase-like nanomaterial promotes autophagy and reprograms macrophages for cancer immunotherapy.

Macrophages are plastic and play a key role in the maintenance of tissue homeostasis. In cancer progression, macrophages also take part in all processes, from initiation to progression, to final tumor metastasis. Although energy deprivation and autophagy are widely used for cancer therapy, most of these strategies do not target macrophages, resulting in undesired effects and unsatisfactory outcomes for cancer immunotherapy. Herein, we developed a lanthanum nickel oxide (LNO) nanozyme with phosphatase-like activity for ATP hydrolysis. Meanwhile, the autophagy of macrophages induced by LNO promotes the polarization of macrophages from M2-like macrophages (M2) to M1-like macrophages (M1) and reduces tumor-associated macrophages in tumor-bearing mice, exhibiting the capability of killing tumor-associated macrophages and antitumor effects in vivo. Furthermore, pre-coating the surface of LNO with a myeloid cell membrane significantly enhanced antitumor immunity. Our findings demonstrate that phosphatase-like nanozyme LNO can specifically induce macrophage autophagy, which improves therapeutic efficacy and offers valuable strategies for cancer immunotherapy.

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.

Stereoselective coronas regulate the fate of chiral gold nanoparticles in vivo.

It is unknown how the identity provided by protein coronas on the surface of chiral nanoparticles determines their blood circulation, distribution, and clearance fates of the nanoparticles in vivo. Here, we attempt to investigate how the mirrored surface of gold nanoparticles with distinct chirality reshapes the coronal composition that mediates their subsequent clearance from blood and biodistribution. We found that chiral gold nanoparticles exhibited surface chirality-specific recognition for the coronal components, including the lipoproteins, complement components, and acute phase proteins, ultimately resulting in distinct cell uptake and tissue accumulation in vivo. We observed that these stereoselective behaviors were correlated to subgroups of the corona composition that could bind to low-density lipoprotein receptors. Therefore, this study reveals how chirality-specific protein compositions selectively recognize and interact with cell receptors for chirality-mediated tissue accumulation. This study will deepen our understanding of how chiral nanoparticles/nanomedicine/nanocarriers interact with biological systems to guide the efficient fabrication of target nanomedicines.

In situ turning defects of exfoliated Ti3C2 MXene into Fenton-like catalytic active sites.

Controllable in situ formation of nanoclusters with discrete active sites is highly desirable in heterogeneous catalysis. Herein, a titanium oxide-based Fenton-like catalyst is constructed using exfoliated Ti3C2 MXene as a template. Theoretical calculations reveal that a redox reaction between the surface Ti-deficit vacancies of the exfoliated Ti3C2 MXene and H2O2 molecules facilitates the in situ conversion of surface defects into titanium oxide nanoclusters anchoring on amorphous carbon (TiOx@C). The presence of mixed-valence Tiδ+ (δ = 0, 2, 3, and 4) within TiOx@C is confirmed by X-ray photoelectron spectroscopy (XPS) and X-ray absorption fine structure (XAFS) characterizations. The abundant surface defects within TiOx@C effectively promote the generation of reactive oxygen species (ROS) leading to superior and stable Fenton-like catalytic degradation of atrazine, a typical agricultural herbicide. Such an in situ construction of Fenton-like catalysts through defect engineering also applies to other MXene family materials, such as V2C and Nb2C.

Penetration and translocation of functional inorganic nanomaterials into biological barriers.

With excellent physicochemical properties, inorganic nanomaterials (INMs) have exhibited a series of attractive applications in biomedical fields. Biological barriers prevent successful delivery of nanomedicine in living systems that limits the development of nanomedicine especially for sufficient delivery of drugs and effective therapy. Numerous researches have focused on overcoming these biological barriers and homogeneity of organisms to enhance therapeutic efficacy, however, most of these strategies fail to resolve these challenges. In this review, we present the latest progress about how INMs interact with biological barriers and penetrate these barriers. We also summarize that both native structure and components of biological barriers and physicochemical properties of INMs contributed to the penetration capacity. Knowledge about the relationship between INMs structure and penetration capacity will guide the design and application of functional and efficient nanomedicine in the future.

In situ analysis of nanoparticle soft corona and dynamic evolution.

How soft corona, the protein corona's outer layer, contributes to biological identity of nanomaterials is largely because capturing protein composition of the soft corona in situ remains challenging. We herein develop an in situ Fishing method that can monitor the dynamic formation of protein corona on ultra-small chiral Cu2S nanoparticles (NPs) allowing us to directly separate and identify the corona protein composition. Our method detects spatiotemporal processes in the evolution of hard and soft coronas on chiral NPs, revealing subtle differences in NP - protein interactions even within several minutes. This study highlights the importance of in situ and dynamic analysis of soft/hard corona, provides insights into the role of soft corona in mediating biological responses of NPs, and offers a universal strategy to characterize soft corona to guide the rational design of biomedical nanomaterials.

A nanomaterial targeting the spike protein captures SARS-CoV-2 variants and promotes viral elimination.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.

Induced Autophagy of Macrophages and the Regulation of Inflammatory Effects by Perovskite Nanomaterial LaNiO3.

Perovskite nanomaterials (NMs) possess excellent physicochemical properties and have promising applications in light-emitting diodes (LEDs), lasers, photodetectors, and artificial synapse electronics. Potential exposure to these NMs happens in the manufacture and application of the perovskite-based products, however, the biological safety of these NMs is still unknown. Here, we used the LaNiO3 NM (LNO), a typical kind of perovskite nanostructures to study the interaction with macrophages (J774A.1) and to explore its biological effects at the cellular level. Firstly, we characterized the properties of LNO including the size, shape, and crystal structure using Transmission electronic microscope (TEM), Dynamic lighting scattering (DLS), and X-ray diffraction (XRD). Secondly, to gain a better understanding of the biological effect, we evaluated the effect of LNO on cell viability and found that LNO induced cell autophagy at a concentration of 5 µg/ml and influenced the inflammatory response based on RT-PCR result. Finally, we demonstrated the mechanism that LNO causes cell autophagy and immune response is probably due to the metal ions released from LNO in acidic lysosomes, which triggered ROS and increased lysosomal membrane permeation. This study indicates the safety aspect of perovskite NMs and may guide the rational design of perovskite NMs with more biocompatibility during their manufacture and application.

Immunological Responses Induced by Blood Protein Coronas on Two-Dimensional MoS2 Nanosheets.

Two-dimensional (2D) nanosheets (NSs) have a large surface area, high surface free energy, and ultrathin structure, which enable them to more easily penetrate biological membranes and promote adsorption of drugs and proteins. NSs are capable of adsorbing a large amount of blood proteins to form NSs-protein corona complexes; however, their inflammatory effects are still unknown. Therefore, we investigated the pro-inflammatory effect of 2D model nanosheet structures, molybdenum disulfide (MoS2), and the MoS2 NSs-protein complexes with four abundant proteins in human blood, i.e., human serum albumin (HSA), transferrin (Tf), fibrinogen (Fg), and immunoglobulin G (IgG). The interactions between the NSs and the proteins were analyzed by quantifying protein adsorption, determining binding affinity, and correlating structural changes in the protein corona with the uptake of NSs by macrophages and the subsequent inflammatory response. Although all of the NSs-protein complexes induced inflammation, IgG-coated and Fg-coated NSs triggered much stronger inflammatory effects by producing and releasing more cytokines. Among the four proteins, IgG possessed the highest proportion of ß-sheets and led to fewer secondary structure changes on the MoS2 nanosheets. This can facilitate uptake and produce a stronger pro-inflammatory response in macrophages due to the recognition of an NSs-IgG complex by Fc gamma receptors and the subsequent activation of the NF-κB pathways. Our results demonstrate that the blood protein components contribute to the inflammatory effects of nanosheets and provide important insights for the nanosafety evaluation and the rational design of nanomedicines in the future.

Understanding the Chemical Nature of Nanoparticle-Protein Interactions.

The formation of a protein corona has been considered a pitfall in the clinical translation of nanomedicines. Hence, interdisciplinary studies on corona characterization are critically essential. A deep understanding of the formation of hard and soft protein coronas upon in vivo administration of nanoparticles is vital. The protein corona gives the nanoplatform a new biological identity. Furthermore, the control of and mechanistic understanding of corona formation as it is regulated by the physicochemical properties of nanoparticles is crucial for developing safe nanomedicines. A growing number of analytical techniques have been developed in the past decade for examining NP-protein interactions, contributing to a better understanding of protein corona formation on the surface of nanoparticles. In this Review, we summarize the latest developments in the in vivo and in vitro study of dynamic protein corona formation. Insights derived from techniques used to visualize, quantify, and define protein coronas, as well as the methods for examining the kinetics and structural changes of coronal proteins, are discussed. The potential challenges and future perspectives in the study of protein corona formation and its effects on biological behavior and applications of therapeutic nanomaterials are also provided.

Precision Nanomedicine Development Based on Specific Opsonization of Human Cancer Patient-Personalized Protein Coronas.

When a nanomedicine is administrated into the human body, biomolecules in biological fluids, particularly proteins, form a layer on the surface of the nanoparticle known as a "personalized protein corona". An understanding of the formation and behavior of the personalized protein corona not only benefits the nanotherapy treatment efficacy but also can aid in disease diagnosis. Here we used Gd@C82(OH)22 nanoparticles, a nanomedicine effective against several types of cancer, as a model nanomedicine to investigate the natural protein fingerprint of the personalized protein corona formed in 10 human lung squamous cell carcinoma patients. Our analysis revealed a specific biomarker, complement component C1q, in lung cancer personalized protein coronas, abundantly bound to Gd@C82(OH)22 NPs. This binding altered the secondary structure of C1q protein and led to the activation of an innate immune response, which could be exploited for cancer immune therapy. On the basis of this finding, we provide a new strategy for the development of precision nanomedicine derived from opsonization of a unique protein fingerprint within patients. This approach overcomes the common pitfall of protein corona formation and exploits the corona proteins to generate a precision nanomedicine and diagnostic tool.

Immobilized Ferrous Ion and Glucose Oxidase on Graphdiyne and Its Application on One-Step Glucose Detection.

Graphdiyne (GDY) is a novel two-dimensional (2D) carbon allotrope with sp-hybridized carbon atoms and hexagonal rings. Because of its unique structure and electronic property, GDY was reported as a promising candidate applied in energy storage, catalysis, biosensing and so on. However, using GDY as a platform to immobilize metal ion or enzyme was still not reported. Here, we presented a GDY-based composite with dual-enzyme activity by immobilizing ferrous ion and glucose oxidase onto GDY sheet. GDY showed great adsorption capacity and maintained the high catalytic activity of ferrous ion. The ferrous ion preferred to adsorb in between the neighboring two C-C triple bonds of GDY with lower adsorption energy (-5.64 eV) if compared to graphene (-1.69 eV). Meanwhile, GDY exhibited the ability of adsorbing glucose oxidase while did not obviously influence the structure and catalytic activity of the enzyme. The as-prepared composite was successfully used in one-step blood glucose detection. This work provides a new insight on ion and enzyme immobilization by 2D material.