Self-assembled Nanoparticles Research Articles

Ferritin nanoparticle-based Nipah virus glycoprotein vaccines elicit potent protective immune responses in mice and hamsters

Nipah virus (NiV) is a zoonotic paramyxovirus in the genus Henipavirus that is prevalent in Southeast Asia. NiV leads to severe respiratory disease and encephalitis in humans and animals, with a mortality rate of up to 75%. Despite the grave threat to public health and global biosecurity, no medical countermeasures are available for humans. Here, based on self-assembled ferritin nanoparticles (FeNPs), we successfully constructed two candidate FeNP vaccines by loading mammalian cells expressing NiV sG (residues 71–602, FeNP-sG) and Ghead (residues 182–602, FeNP-Ghead) onto E. coli-expressed FeNPs (FeNP-sG and FeNP-Ghead, respectively) through Spycatcher/Spytag technology. Compared with sG and Ghead alone, FeNP-sG and FeNP-Ghead elicited significant NiV specific neutralizing antibody levels and T-cell responses in mice, whereas the immune response in the FeNP-sG immunized group was greater than that in the FeNP-Ghead group. These results further demonstrate that sG possesses greater antigenicity than Ghead and that FeNPs can dramatically enhance immunogenicity. Furthermore, FeNP-sG provided 100% protection against NiV challenge in a hamster model when it was administered twice at a dose of 5 μg/per animal. Our study provides not only a promising candidate vaccine against NiV, but also a theoretical foundation for the design of a NiV immunogen for the development of novel strategies against NiV infection.

Advancements in Micellar Formulation: Drug Delivery Vehicle for Water-Insoluble Drugs

: Micellar systems, particularly polymeric micelles, have emerged as a promising drug delivery vehicle for water-insoluble compounds. Polymeric micelles, self-assembled nanostructures made from amphiphilic block copolymers, have emerged as a promising drug delivery vehicle for water-insoluble compounds. These micelles offer high drug loading capacity, stability, and the ability to solubilize large amounts of hydrophobic drugs, making them an attractive option for delivering drugs with limited solubility and bioavailability. Their small size allows for efficient delivery and targeting of specific tissues or cells, reducing off-target effects and improving therapeutic outcomes. This review provides a brief overview of drug delivery system challenges, solutions, techniques of micelle formation, factors affecting micelle stability and drug loading, applications, pharmacokinetics and pharmacodynamics of micellar formulations, toxicological considerations, limitations, recent advancements, and clinical trials of micelles in drug delivery. By addressing these key aspects, this review seeks to provide a comprehensive understanding of the current status and prospects of polymeric micelles as a promising drug delivery system.

Two-Regime Conformation of Grafted Polymer on Nanoparticle Determines Symmetry of Nanoparticle Self-Assembly.

One of the key design factors that regulate the properties of grafted nanoparticles (GNPs) and their self-assembly is the conformation of the grafted polymer. On the curved surface of the GNP core, the conformation of the polymer chain is not uniform in the radial direction. The segment is a non-Gaussian chain in the concentrated polymer brush (CPB) regime near the interface between GNP core and grafted polymer, while it is less constrained in the semidilute polymer brush (SDPB) regime near the surface of GNP. Here, the property of polymer conformation showing crossover behavior at the CPB/SDPB threshold through the coarse-grain molecular dynamics simulation of nanoparticles with explicit grafted chains is explored. Moreover, the self-assembly structure depends on the effective softness, which is defined as a function of the threshold of two regimes estimated from the conformation of the polymer.

An attachment glycoprotein nanoparticle elicits broadly neutralizing antibodies and protects against lethal Nipah virus infection

Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

Hydrogen generation by water splitting of formic acid assisted supramolecular self-assembled g-C3N4 nanostructures

The photocatalytic hydrolysis reaction primarily unfolds on the material's surface, making the material's morphology and microstructure critical for the catalytic efficiency of photocatalysts. In this paper, a formic acid-assisted melamine hydrothermal self-assembly method is explored to prepare g-C3N4 photocatalysts with a unique morphology. The impact of sintering temperature on the morphology of the g-C3N4 photocatalysts are explored and the effect of formic acid concentration on the XRD and FTIR was analyzed. Findings reveal that the g-C3N4 nanostructures photocatalyst possesses fibrous tubular and nanosheet structures, boasting a heightened specific surface area (32.9 m2/g) and a more refined graphite-like crystalline framework. When synthesized with a 0.15 M concentration of formic acid, the g- C3N4 nanostructured photocatalyst achieved a hydrogen production rate (1289.4 μmol h−1 g−1), which is approximately 4.8 times greater than that of bulk g-C3N4 (264.7 μmol h−1 g−1). This work provides a simple method for preparing high-performance g-C3N4 based photocatalysts for visible light hydrolysis hydrogen production.

Interpretable Structural Evaluation of Metal-Oxide Nanostructures in Scanning Transmission Electron Microscopy (STEM) Images via Persistent Homology.

Persistent homology is a powerful tool for quantifying various structures, but it is equally crucial to maintain its interpretability. In this study, we extracted interpretable geometric features from the persistent diagrams (PDs) of scanning transmission electron microscopy (STEM) images of self-assembled Pt-CeO2 nanostructures synthesized under different annealing conditions. We focused on PD quadrants and extracted five interpretable features from the zeroth and first PDs of nanostructures ranging from maze-like to striped patterns. A combination of hierarchical clustering and inverse analysis of PDs reconstructed by principal component analysis through vectorization of the PDs highlighted the importance of the number of arc-like structures of the CeO2 phase in the first PDs, particularly those that were smaller than a characteristic size. This descriptor enabled us to quantify the degree of disorder, namely the density of bends, in nanostructures formed under different conditions. By using this descriptor along with the width of the CeO2 phase, we classified 12 Pt-CeO2 nanostructures in an interpretable way.

A Single-Component Multilayered Self-Assembling Protein Nanoparticle Vaccine Based on Extracellular Domains of Matrix Protein 2 against Both Influenza A and B.

The development of an effective and broadly protective influenza vaccine against circulating and emerging strains remains elusive. In this study, we evaluated a potentially universal influenza vaccine based on single-component self-assembling protein nanoparticles (1c-SApNPs) presenting the conserved matrix protein 2 ectodomain (M2e) from influenza A and B viruses (IAV and IBV, respectively). We previously designed a tandem antigen comprising three IAV M2e domains of human, avian/swine, and human/swine origins (termed M2ex3). The M2ex3-presenting 1c-SApNPs conferred complete protection in mice against sequential lethal challenges with H1N1 and H3N2. To broaden this protection to cover IBVs, we designed a series of antigens incorporating different arrangements of three IAV M2e domains and three copies of IBV M2e. Tandem repeats of IAV and IBV (termed influenza A-B) M2e arrayed on the I3-01v9a 60-mer 1c-SApNP, when formulated with an oil-in-water emulsion adjuvant, generated greater M2e-specific immunogenicity and protective efficacy than the soluble influenza A-B M2e trimer, indicated by higher survival rates and reduced weight loss post-challenge. Importantly, one of the influenza A-B M2e SApNP constructs elicited 100% protection against a lethal influenza A/Puerto Rico/8/1934 (H1N1) challenge in mice and 70% protection against a lethal influenza B/Florida/4/2006 (Yamagata lineage) challenge, the latter of which has not been reported in the literature to date. Our study thus provides a promising M2e-based single-component universal vaccine candidate against the two major types of influenza virus circulating in humans.

Endogenous capsid-forming protein ARC for self-assembling nanoparticle vaccines

The application of nanoscale scaffolds has become a promising strategy in vaccine design, with protein-based nanoparticles offering desirable avenues for the biocompatible and efficient delivery of antigens. Here, we presented a novel endogenous capsid-forming protein, activated-regulated cytoskeleton-associated protein (ARC), which could be engineered through the plug-and-play strategy (SpyCatcher3/SpyTag3) for multivalent display of antigens. Combined with the self-assembly capacity and flexible modularity of ARC, ARC-based vaccines elicited robust immune responses against Mpox or SARS-CoV-2, comparable to those induced by ferritin-based vaccines. Additionally, ARC-based nanoparticles functioned as immunostimulants, efficiently stimulating dendritic cells and facilitating germinal center responses. Even without adjuvants, ARC-based vaccines generated protective immune responses in a lethal challenge model. Hence, this study showed the feasibility of ARC as a novel protein-based nanocarrier for multivalent surface display of pathogenic antigens and demonstrated the potential of exploiting recombinant mammalian retrovirus-like protein as a delivery vehicle for bioactive molecules.Graphic

Development of fucoidan/polyethyleneimine based sorafenib-loaded self-assembled nanoparticles with machine learning and DoE-ANN implementation: Optimization, characterization, and in-vitro assessment for the anticancer drug delivery

This study aims to develop sorafenib-loaded self-assembled nanoparticles (SFB-SANPs) using the combined approach of artificial neural network and design of experiments (ANN-DoE) and to compare it with other machine learning (ML) models. The central composite design (CCD) and ML algorithms were used to screen the effects of concentrations of both the polymers (polyethyleneimine and fucoidan) on the outcome responses, i.e., particle size and entrapment efficiency with defined constraints. The prediction from different ML models (bootstrap forest, K-nearest neighbors, artificial neural network, generalized regression-lasso and support vector machines) were compared with ANN-DoE model. The ANN-DoE model showed better accuracy and predictability and outperformed all the other models. This depicted that the concept of using ANN and DoE combination approach provided the best, uncomplicated and cost-effective way to optimized the nanoformulations. The optimized formulation generated from the ANN-DoE combined model was further evaluated for characterization and anticancer activity. The optimized SFB-SANPs were prepared using the polyelectrolyte complexation method with Polyethyleneimine (PEI) as a cationic polymer and fucoidan (FCD) as an anionic. The SFB-SANPs were nanometric in size (280.4 ± 0.089 nm) and slightly anionic in nature (zeta potential = −6.03 ± 0.92 mV) with an encapsulation efficiency of 95.56 ± 0.30 %. The drug release from SFB-SANPs was controlled and sustained in the cancer microenvironment (pH 5.0). The SFB-SANPs were compatible with red blood cells (RBCs), and the % hemolysis was found to be <5.0 %. The anticancer activity of the SFB-SANPs exhibited an IC50 at 2.017 ± 0.516 μM against MDMB-231 cells, showing a significantly high inhibitory effect on breast cancer cell lines. Therefore, the nanocarriers developed using various ML tools inherit a huge promise in anticancer drug delivery.

Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming

Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces. Specifically, our strategy permits controlled assembly of small poly(β-amino ester)/messenger ribonucleic acid (mRNA) nanoparticles into particles with a size that is kinetically tunable between 200 and 1,000 nm with high colloidal stability in physiological media. We found that assembled particles with an average size of 400 nm safely and most efficiently transfect monocytes following intravenous administration and mediate their differentiation into macrophages in the periphery. When a CpG adjuvant is co-loaded into the particles with an antigen mRNA, the monocytes differentiate into inflammatory dendritic cells and prime adaptive anticancer immunity in the tumor-draining lymph node. This platform technology offers a unique ligand-independent, particle-size-mediated strategy for preferential mRNA delivery and enables therapeutic paradigms via monocyte programming.

Self-Regulated Assembly and Disassembly of Gold Nanoparticles for Low-Temperature Time Indication.

The color-changing self-assembly and autonomous disassembly of colloidal gold nanoparticles (AuNPs) is reported by simply mixing negatively charged phosphine ligand-capped AuNPs with partially oxidized polyethylene glycol (PEG). The assembly of AuNPs is initiated by PEG adsorption, which disrupts the hydration layer of AuNPs, leading to depletion attraction and reduction of hydration repulsion among the AuNPs. The oxidative species in PEG subsequently oxidize and remove the charged ligands from the AuNP surface, resulting in a decrease and reversal of the negative surface charge. This causes the PEG to adsorb on AuNPs in a tighter and more direct manner, providing strong steric shielding to the AuNPs, thereby triggering the disassembly of the AuNP assemblies. The self-regulated assembly-disassembly process can be tuned widely by controlling chemical conditions of PEG, nanoparticle concentration, and the environmental conditions, suggesting potential applications as colorimetric time-temperature indicators for food and medicine storage conditions. As a proof of concept, it is demonstrated that the lifetime of the color-changing assembly-disassembly process can be extended from tens of minutes to weeks when subjected to a refrigerated environment, with tunability achievable through varying polymer conditions and storage atmospheres.

Development of a Ferritin-Based Nanoparticle Vaccine against Classical Swine Fever.

The occurrence of classical swine fever (CSF) poses a significant threat to the global swine industry. Developing an effective and safe vaccine is crucial for preventing and controlling CSF. Here, we constructed self-assembled ferritin nanoparticles fused with the classical swine fever virus (CSFV) E2 protein and a derived B cell epitope (Fe-E2B) using a baculovirus expression system (BVES), demonstrating enhanced immunogenicity. Furthermore, we provide a detailed evaluation of the immunological efficacy of the FeE2B in rabbits. The results showed that robust and sustained antibody responses were detected in rabbits immunized with the Fe-E2B nanoparticle vaccine, comparable to those elicited by commercially available vaccines. Additionally, we demonstrated that the vaccine effectively activated crucial immune factors IFN-γ and IL-4 in vivo, increasing their levels by 1.41-fold and 1.39-fold, respectively. Immunization with Fe-E2B enabled rabbits to avoid viremia and stereotypic fever after CSFV challenge. In conclusion, this study highlights the potential of ferritin nanoparticles as antigen-presenting carriers to induce robust immune responses, proposing a candidate vaccine strategy for the prevention and control of CSF.

Epitopes screening and vaccine molecular design of PEDV S protein based on immunoinformatics

Porcine epidemic diarrhea virus (PEDV) is a serious disease that poses a significant threat to the pig industry. This study focused on analyzing the Spike protein of PEDV, which harbors crucial antigenic determinants, in identifying dominant epitopes. Immunoinformatics tools were used to screen for B-cell, CD4+ and CD8+ predominance epitopes. These epitopes were then connected to the N-terminal of ferritin to form a self-assembled nanoparticle vaccine. Various physical and chemical properties of the candidate vaccine were analyzed, including secondary structure prediction, tertiary structure modeling, molecular docking, immune response simulation and computer cloning. The results demonstrated that the candidate vaccine was antigenic, soluble, stable, non-allergic, and formed a stable complex with the target receptor TLR-3. Immune simulation analysis showed that the candidate vaccine effectively stimulated both cellular and humoral reactions, leading to increased related cytokines production. Furthermore, efficient and stable expression of the candidate vaccine was achieved through reverse translation in the Escherichia coli K12 expression system following codon optimization and in silico cloning. The developed nanoparticle candidate vaccine in this study holds promise as an effective PEDV vaccine candidate, offering a new approach for the research, development and improvement of vaccines targeting porcine enteric diarrhea coronavirus.

Dynamic Gas-Bridged Bond: An Opportunity of Fabricating Dynamic Assembled Materials with Gas.

Gas molecules, as a family of unique polyatomic building blocks, have long been considered hard to involve in molecular assembly or construct assembled materials due to their structural simplicity yet paucity of defined interacting sites. To solve this non-trivial challenge, a core idea is to break the limit of current ways of bonding gas molecules, endowing them with new modes of interactions that match the basic requirements of molecular assembly. In recent years, a new concept, named the dynamic gas-bridged bond (DGB), has emerged, which allows for gas molecules to constitute a dynamic bridging structure between other building blocks with the aid of frustrated Lewis pairs. This makes it possible to harness gas in a supramolecular or dynamic manner. Herein, this perspective discusses distinct dynamic natures of DGBs and manifests their particular functions in various fields, including the control of molecular/polymeric self-assembly nanostructures, creation of multidimensional assembled materials, and recyclable catalysts. The future research direction and challenges of dynamic gas-bridged chemistry toward gas-programmed self-assembly and gas-constructed adaptive materials are highlighted.

Glycopolymeric Micellar Nanoparticles for Platelet-Mediated Tumor-Targeted Delivery of Docetaxel for Cancer Therapy.

The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.

Redox-sensitive disulfide-bridged self-assembled nanoparticles of dexamethasone with high drug loading for acute lung injury therapy

Acute lung injury (ALI) arises from an excessive inflammatory response, usually progressing to acute respiratory distress syndrome (ARDS) if not promptly addressed. There is currently a limited array of effective treatments available for ALI. In this study, we developed disulfide bond-bridged prodrug self-assembled nanoparticles (referred to as DSSS NPs). These nanoparticles were consisted of Dexamethasone (Dex) and stearic acid (SA), and were designed to target and treat ALI. DSSS NPs demonstrated a substantial drug loading capacity with 37.75 % of Dex, which is much higher than conventional nanomedicines (usually < 10 %). Moreover, they exhibited the potential to specifically target injured lung tissue and inflammatory microenvironment-responsive release drugs. Consequently, DSSS NPs reduced significantly the levels of pro-inflammatory cytokines and tissue damage in mice with ALI induced by lipopolysaccharide (LPS). Overall, DSSS NPs offer a promising strategy for treatment of acute lung injury.

Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly.

Ionizable lipid-containing lipid nanoparticles (LNPs) have enabled the delivery of RNA for a range of therapeutic applications. In order to optimize safe, targeted, and effective LNP-based RNA delivery platforms, an understanding of the role of composition and pH in their structural properties and self-assembly is crucial, yet there have been few computational studies of such phenomena. Here we present a coarse-grained model of ionizable lipid and mRNA-containing LNPs. Our model allows access to the large length- and time-scales necessary for LNP self-assembly and is mapped and parametrized with reference to all-atom structures and simulations of the corresponding components at compositions typical of LNPs used for mRNA delivery. Our simulations reveal insights into the dynamics of self-assembly of such mRNA-encapsulating LNPs, as well as the subsequent pH change-driven LNP morphology and release of mRNA.

M2 macrophage-polarized anti-inflammatory microneedle patch for accelerating biofilm-infected diabetic wound healing via modulating the insulin pathway

Macrophages play a pivotal role in the healing of diabetic ulcers. The sustained elevation of glucose levels damages the insulin signaling pathway in macrophages, leading to dysfunctional macrophages that struggle to transition from pro-inflammatory (M1) to reparative (M2) states. Therefore, modulating macrophage inflammatory responses via the insulin pathway holds promise for diabetic ulcer treatment. Additionally, the presence of biofilm impedes drug penetration, and the resulting immunosuppressive microenvironment exacerbates the persistent infiltration of pro-inflammatory M1 macrophages. Therefore, we designed an array of dissolvable microneedle (denoted as NPF@MN) loaded with self-assembled nanoparticles that could deliver NPF nanoparticles, acid-sensitive NPF-releasing Protocatechualdehyde (PA) with hypoglycemic and insulin-like effects, regulating macrophage polarization to an anti-inflammatory M2 phenotype. Additionally, this study extensively examined the mechanism by which NPF@MN accelerates the healing of diabetic ulcers through the activation of the insulin signaling pathway. Through RNA-seq and GSEA analysis, we identified a reduction in the expression of pathway-related factors such as IR, IRS-1, IRS-2, and SHC. Our work presents an innovative therapeutic approach targeting the insulin pathway in diabetic ulcers and underscores its translational potential for clinical management.

Isoalantolactone/hydroxamic acid hybrids as potent dual STAT3/HDAC inhibitors and self-assembled nanoparticles for cancer therapy

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products.

Functional Materials of 2D Self-Assembled Nanoparticle Monolayers: Preparation and Application

Functional Materials of 2D Self-Assembled Nanoparticle Monolayers: Preparation and Application