Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions.

Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio-nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio-nano interactions and pave the way forward in the development of more effective cancer nanomedicines.

Microfluidic Nanoparticles for Drug Delivery.

Nanoparticles (NPs) have attracted tremendous interest in drug delivery in the past decades. Microfluidics offers a promising strategy for making NPs for drug delivery due to its capability in precisely controlling NP properties. The recent success of mRNA vaccines using microfluidics represents a big milestone for microfluidic NPs for pharmaceutical applications, and its rapid scaling up demonstrates the feasibility of using microfluidics for industrial-scale manufacturing. This article provides a critical review of recent progress in microfluidic NPs for drug delivery. First, the synthesis of organic NPs using microfluidics focusing on typical microfluidic methods and their applications in making popular and clinically relevant NPs, such as liposomes, lipid NPs, and polymer NPs, as well as their synthesis mechanisms are summarized. Then, the microfluidic synthesis of several representative inorganic NPs (e.g., silica, metal, metal oxide, and quantum dots), and hybrid NPs is discussed. Lastly, the applications of microfluidic NPs for various drug delivery applications are presented.

Social-path embedding-based transformer for graduation development prediction.

As the education of students attracts more and more attention, the task of graduation development prediction has gradually become a hot topic in academia and industry. The task of graduation development prediction aims to predict the employment category of students in advance via academic achievement data, which can help administrators understand students' learning status and set up a reasonable learning plan. However, existing research ignores the potential impact of social relationships on students' graduation development choices. To fully explore social relationships among students, we propose a Social-path Embedding-based Transformer Neural Network (SPE-TNN) for the task of graduation development prediction in this paper. Specifically, SPE-TNN is divided into the Social-path selection layer, the Social-path embedding layer, the Transformer layer, and the Multi-layer projection layer. Firstly, the Social-path selection layer is designed to find social relationships that impact graduation development and embed them into the student's performance features through the Social-path embedding layer. Secondly, the Transformer layer is adopted to balance the weights of the students' features. Finally, the Multi-layer projection layer is used to achieve the student graduation development prediction. Experimental results on the real-world datasets show that SPE-TNN outperforms the existing popular approaches.

Development of Core-Shell Nanoparticle Drug Delivery Systems Based on Biomimetic Mineralization.

Among various drug-delivery systems, core-shell nanoparticles have many advantages. Inspired by nature, biomimetic synthesis has emerged as a new strategy for making core-shell nanoparticles in recent years. Biomimetic mineralization is the process by which living organisms produce minerals based on biomolecule templating that leads to the formation of hierarchically structured organic-inorganic materials. In this minireview, we mainly focus on the synthesis of core-shell nanoparticle drug-delivery systems by biomimetic mineralization. We review various biomimetic mineralization methods for fabricating core-shell nanoparticles including silica-based, calcium-based and other nanoparticles, and their applications in drug delivery. We also summarize strategies for drug loading in the biomolecule-mineralized core-shell NPs. Current challenges and future directions are also discussed.

Optical chaotic flip-flop operations with multiple triggering under clock synchronization in the VCSEL with polarization-preserved optical injection.

We investigate the evolution of nonlinear dynamic behaviors of two polarization components (x-PC and y-PC), as well as the interplay of polarization bistability and injection strength in the vertical-cavity surface-emitting laser (VCSEL) with polarization-preserved optical injection. We explore a new threshold mechanism to judge two logic outputs encoded in different dynamic behaviors of the x-PC and y-PC emitted by the VCSEL with polarization-preserved optical injection. We demonstrate implementations of two parallel optical chaotic reset-set flip-flop operations and two parallel chaotic toggle flip-flop operations that are synchronized by a clock signal and response for as short as 1 ns bit time. We further observe the reconfiguration of these two kinds of flip-flop operations with clock synchronization in different time periods by controlling the duration-time of the reset (toggle) signal with high-level. The probability of the correct trigger responses for these two kinds of flip-flop operations is controlled by the interplay of the duration-time of the reset (toggle) signal and the noise strength of the spontaneous emission. The probability that is equal to 1 for the reset-set flip-flop operations occurs in the long duration-time of the reset (toggle) signal ranging from 480 ps to 592 ps. The probability with 1 for the toggle flip-flop operations takes place in the short duration-time between 116 ps and 170 ps. Moreover, these two kinds of flip-flop operations have strong robust to the spontaneous emission noise. The optical chaotic flip-flop operation device with clock synchronization and reconfigurable trigger function proposed in our scheme offers interesting perspectives for applications where noise is unavoidable and synchronized multiple triggering is required.

J-Aggregate-Based FRET Monitoring of Drug Release from Polymer Nanoparticles with High Drug Loading.

Understanding drug-release kinetics is critical for the development of drug-loaded nanoparticles. We developed a J-aggregate-based Förster-resonance energy-transfer (FRET) method to investigate the release of novel high-drug-loading (50 wt %) nanoparticles in comparison with low-drug-loading (0.5 wt %) nanoparticles. Single-dye-loaded nanoparticles form J-aggregates because of the high dye-loading (50 wt %), resulting in a large red-shift (≈110 nm) in the fluorescence spectrum. Dual-dye-loaded nanoparticles with high dye-loading using FRET pairs exhibited not only FRET but also a J-aggregate red-shift (116 nm). Using this J-aggregate-based FRET method, dye-core-polymer-shell nanoparticles showed two release processes intracellularly: the dissolution of the dye aggregates into dye molecules and the release of the dye molecules from the polymer shell. Also, the high-dye-loading nanoparticles (50 wt %) exhibited a slow release kinetics in serum and relatively quick release in cells, demonstrating their great potential in drug delivery.

Parthenolide regulates oxidative stress-induced mitophagy and suppresses apoptosis through p53 signaling pathway in C2C12 myoblasts.

Muscle redox disturbances and oxidative stress have emerged as a common pathogenetic mechanism and potential therapeutic intervention in some muscle diseases. Parthenolide (PTL), a sesquiterpene lactone found in large amounts in the leaves of feverfew, possesses anti-inflammatory, anti-migraine, and anticancer properties. Although PTL was reported to alleviate cancer cachexia and improve skeletal muscle characteristics in a cancer cachexia model, its actions on oxidative stress-induced damage in C2C12 myoblasts have not been reported and the regulatory mechanisms have not yet been defined. In our study, PTL attenuated H2 O2 -induced growth inhibition and morphological changes. Furthermore, PTL exhibited scavenging activity against reactive oxygen species and protected C2C12 cells from apoptosis in response to H2 O2 . Meanwhile, PTL suppressed collapse of the mitochondrial membrane potential, thereby contributing to normalizing H2 O2 -induced autophagy flux and mitophagy, correlating with inhibiting degradation of mitochondrial marker protein TIM23, the increase in LC3-II expression and the reduction of mitochondria DNA. Besides its protective effect on mitochondria, PTL also prevented H2 O2 -induced lysosomes damage in C2C12 cells. In addition, the phosphorylation of p53, cathepsin B, and Bax/Bcl-2 protein levels, and the translocation of Bax from the cytosol to mitochondria induced by H2 O2 in C2C12 cells was significantly reduced by PTL. In conclusion, PTL modulates oxidative stress-induced mitophagy and protects C2C12 myoblasts against apoptosis, suggesting a potential protective effect against oxidative stress-associated skeletal muscle diseases.

Real-time ranging of the six orientational targets by using chaotic polarization radars in the three-node VCSEL network.

We propose a novel scheme of the real-time ranging for the six orientational targets based on the vertical cavity surface-emitting laser (VCSEL) network with three nodes. In the scheme, we explore a method to realize the globally complete chaotic synchronization (GCCS) of the network with different channel delays. Under the GCCS, we use the six chaotic polarization radars for the ranging of the six orientational targets based on Hilbert transform theory. It is found that the ranging of the six orientational targets has good performance, such as real-time stability and high accuracy, and the absolute errors of the ranging reach millimeter magnitude. Moreover, all relative errors are small and less than 11%.

Optical chaotic data-selection logic operation with the fast response for picosecond magnitude.

We investigate the evolution of nonlinear dynamic behaviors of two polarization components (x-PC and y-PC), as well as the interplay of polarization bistability, frequency detuning and injection strength in the vertical cavity surface emitting laser with optical injection. Specifically, by encoding two logic inputs and one clock input in the amplitude of the light from a sampled grating distributed Bragg reflector laser, and by decoding two output logic responses from the x-PC and y-PC emitted by the laser, we demonstrate two parallel data-selection computing. The correct logic output encoded in two emitted PCs response for as short as 100 ps bit time and the response bit time of the correct logic output encoded in the y-PC may be 67 ps by the optimization of the injection strength. The probability of a correct response is controlled by the interplay of the bit time, the injection strength and noise strength, and is equal to 1 in a wide region of the injection strength and noise strength. The chaotic data-selection computing in an optically VCSEL offer interesting perspectives for applications where noise is unavoidable and fast switching is required.

Bioinspired Core-Shell Nanoparticles for Hydrophobic Drug Delivery.

A large range of nanoparticles have been developed to encapsulate hydrophobic drugs. However, drug loading is usually less than 10 % or even 1 %. Now, core-shell nanoparticles are fabricated having exceptionally high drug loading up to 65 % (drug weight/the total weight of drug-loaded nanoparticles) and high encapsulation efficiencies (>99 %) based on modular biomolecule templating. Bifunctional amphiphilic peptides are designed to not only stabilize hydrophobic drug nanoparticles but also induce biosilicification at the nanodrug particle surface thus forming drug-core silica-shell nanocomposites. This platform technology is highly versatile for encapsulating various hydrophobic cargos. Furthermore, the high drug loading nanoparticles lead to better in vitro cytotoxic effects and in vivo suppression of tumor growth, highlighting the significance of using high drug-loading nanoparticles.

Non-chromatographic bioprocess engineering of a recombinant mineralizing protein for the synthesis of silica nanocapsules.

Inspired by nature, synthetic mineralizing proteins have been developed to synthesize various structures of silica-based nanomaterials under environmentally friendly conditions. However, the development of bioprocesses able to assist in the translation of these new materials has lagged the development of the materials themselves. The development of cost-effective and scalable bioprocesses which minimize reliance on chromatography to recover biomolecules from microbial cell factories remains a significant challenge. This paper reports a simplified purification process for a recently reported recombinant catalytic modular (D4S2) protein (M(DPSMKQLADS-LHQLARQ-VSRLEHA)4 EPSRKKRKKRKKRKKGGGY; M 13.3 kDa; pI 10.9), which combines a variant of the established designer biosurfactant protein DAMP4 with a new biomimetic sequence (RKKRKKRKKRKKGGGY), providing for a bi-modular functionality (emulsification and biosilicification). The four-helix bundle structure of the protein has been demonstrated to remain stable and soluble under high temperature and high salt conditions, which confers simplified bioprocessing character. However, the high positive charge on the biosilification sequence necessitates removal of DNA contaminants from crude cell-extract at an early stage in the process by adding poly(ethyleneimine) (PEI). In this process, cellular protein contaminants were selectively precipitated by adding Na2 SO4 to the protein mixture up to a high concentration (1 M) and mixed at high temperature (90°C, 5 min) where D4S2 remained stable and soluble due to its four-helix bundle structure. Further increase of the Na2 SO4 concentration to 1.8 M precipitated, thus separated, D4S2 from residual PEI. The overall yield of the protein D4S2 was 28.8 mg per 800 mL cells (final cultivation OD600 ∼2) which gives an approximate 79% D4S2-protein yield. In comparison with the previously reported chromatographic purification of D4S2 protein (Wibowo et al., 2015), the final yield of D4S2 protein is increased fourfold in this study. The bio-produced protein D4S2 was proved to retain it emulsification and biosilicification functionalities enabling the formation of oil-core silica-shell nanocapsules at near-neutral pH and room temperature without the use of any toxic organic solvents, confirming no adverse effects due to bioprocess simplification. This work demonstrates that, through proper bioprocess engineering including the removal of critical contaminants such as DNA, a more efficient, simple, and scalable purification process can be used for the high-yield bio-production of a recombinant templating protein useful in the synthesis of bio-inspired nanomaterials. This simplified process is expected to be easily adapted to recover other mineralizing helix bundle-based functional proteins from microbial cell factories. Biotechnol. Bioeng. 2017;114: 335-343. © 2016 Wiley Periodicals, Inc.

Biomimetic Silica Nanocapsules for Tunable Sustained Release and Cargo Protection.

Silica nanocapsules have attracted tremendous interest for encapsulation, protection, and controlled release of various cargoes due to their unique hierarchical core-shell structure. However, it remains challenging to synthesize silica nanocapsules having high cargo-loading capacity and cargo-protection capability without compromising process simplicity and biocompatibility properties. Here, we synthesized oil-core silica-shell nanocapsules under environmentally friendly conditions by a novel emulsion and biomimetic dual-templating approach using a dual-functional protein, in lieu of petrochemical surfactants, thus avoiding the necessities for the removal of toxic components. A light- and pH-sensitive compound can be facilely encapsulated in the silica nanocapsules with the encapsulation efficiency of nearly 100%. Release of the encapsulated active from the nanocapsules was not shown an indication of undesired burst release. Instead, the release can be tuned by controlling the silica-shell thicknesses (i.e., 40 and 77 nm from which the cargo released at 42.0 and 31.3% of the initial amount after 32 days, respectively). The release kinetics were fitted well to the Higuchi model, enabling the possibility of the prediction of release kinetics as a function of shell thickness, thus achieving design-for-purpose silica nanocapsules. Furthermore, the nanocapsules showed excellent alkaline- and sunlight-shielding protective efficacies, which resulted in significantly prolonged half-life of the sensitive cargo. Our biomimetic silica nanocapsules provide a nanocarrier platform for applications that demand process scalability, sustainability, and biocompatibility coupled with unique cargo-protection and controlled-release properties.

M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages.

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non-coding RNA taurine-upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3-mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1-like macrophages in tumors, promoted the activation of CD8+ T cells through PD-L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD-L1 and CD47 expressions by acting as a sponge of miR-141 and miR-340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD-L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD-L1 and CD47 in HCC tissues. Moreover, the combination of Tug1-siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.

Alginate-based materials for enzyme encapsulation.

Enzymes are widely used in industry due to their high efficiency and selectivity. However, their low stability during certain industrial processes can result in a significant loss of catalytic activity. Encapsulation is a promising technique that can stabilize enzymes by protecting them from environmental stresses such as extreme temperature and pH, mechanical force, organic solvents, and proteases. Alginate and alginate-based materials have emerged as effective carriers for enzyme encapsulation due to their biocompatibility, biodegradability, and ability to form gel beads through ionic gelation. This review presents various alginate-based encapsulation systems for enzyme stabilization and explores their applications in different industries. We discuss the preparation methods of alginate encapsulated enzymes and analyze the release mechanisms of enzymes from alginate materials. Additionally, we summarize the characterization techniques used for enzyme-alginate composites. This review provides insights into the use of alginate encapsulation as a means of stabilizing enzymes and highlights the potential benefits for various industrial applications.

Bioinspired core-shell silica nanoparticles monitoring extra- and intra-cellular drug release.

Förster resonance energy transfer (FRET) has been widely used for monitoring drug release from nanoparticles (NPs). To understand the drug release from bioinspired drug-core silica-shell NPs, we synthesised two types of NPs using the dual-functional peptide SurSi via biosilicification for the first time, i.e., silica NP conjugated with FRET (Cy3 and Cy5) molecules, and FRET-core (DiO and DiI) silica-shell NP with different shell thicknesses (18 and 41 nm). The release kinetics of these two types of NPs were investigated under different conditions, including fetal bovine serum (FBS) and in cells, to mimic the drug release during blood circulation and intracellularly. Two different drug release mechanisms were identified. Cargo diffusion dominated the release during circulation, while the degradation of silica shell played a key role in drug release intracellularly.

Influence of nanoparticle mechanical property on protein corona formation.

A protein corona forms around nanoparticles when they are intravenously injected into the bloodstream. The composition of the protein corona dictates the interactions between nanoparticles and the biological systems thus their immune evasion, blood circulation, and biodistribution. Here, we report for the first time the impact of nanoparticle stiffness on protein corona formation using a unique emulsion core silica shell nanocapsules library with a wide range of mechanical properties over four magnitudes (700 kPa to 10 GPa). The nanocapsules with different stiffness showed distinct proteomic fingerprints. The protein corona of the stiffest nanocapsules contained the highest amount of complement protein (Complement C3) and immunoglobulin proteins, which contributed to their high macrophage uptake, confirming the important role of nanocapsules stiffness in controlling the protein corona formation thus their in vitro and in vivo behaviors.

Quantitative comparison of different fluorescent dye-loaded nanoparticles.

Labeling nanoparticles with fluorescent dyes is a common approach to investigate their cell uptake and biodistribution, providing valuable information for the preclinical assessment of nanoparticles for drug delivery. However, the underlying assumption that the fluorescence intensity of dye-labeled nanoparticles correlates positively with the amount of nanoparticles taken up by cells might not be valid under some conditions, as it can be affected by many factors including dye dispersion, dye quenching, and material shading. Here we demonstrated that both nanoparticles with hydrophobic dyes encapsulated inside and nanoparticles with hydrophilic dyes conjugated on the particle surface suffer from different degrees of dye quenching, making it challenging for quantitative comparison of cell uptake of different nanoparticles. To address this challenge, we proposed a possible solution for direct comparative studies of dye-labeled nanoparticles. This work provides valuable information for designing and evaluating different nanoparticles for drug delivery applications.

FRET Ratiometric Nanoprobes for Nanoparticle Monitoring.

Fluorescence labelling is often used for tracking nanoparticles, providing a convenient assay for monitoring nanoparticle drug delivery. However, it is difficult to be quantitative, as many factors affect the fluorescence intensity. Förster resonance energy transfer (FRET), taking advantage of the energy transfer from a donor fluorophore to an acceptor fluorophore, provides a distance ruler to probe NP drug delivery. This article provides a review of different FRET approaches for the ratiometric monitoring of the self-assembly and formation of nanoparticles, their in vivo fate, integrity and drug release. We anticipate that the fundamental understanding gained from these ratiometric studies will offer new insights into the design of new nanoparticles with improved and better-controlled properties.

Microfluidic synthesis of curcumin loaded polymer nanoparticles with tunable drug loading and pH-triggered release.

Polymer nanoparticles (NPs) have attracted significant interest in the past years for drug delivery and triggered release. However, it remains a significant challenge to produce polymer NPs with controlled properties and tunable drug loading. Traditional nanoprecipitation often leads to low drug loading. This study reports the development of a new microfluidic nanoprecipitation approach for making polymer NPs with tunable drug loading up to 50%. The synthesized curcumin-loaded shellac NPs remain very stable for the period of our experiments (10 days) under acidic conditions (pH 4.5), but release the payload at neutral pH in a sustained manner. This work provides a new strategy for making drug-loaded polymer NPs with tunable drug loading and triggered release.

Biomimetic core-shell silica nanoparticles using a dual-functional peptide.

Biomimetic nanomaterials have attracted tremendous research interest in the past decade. We recently developed biomimetic core-shell nanoparticles - silica nanocapsules, using a designer dual-functional peptide SurSi under room temperature, neutral pH and without use of any toxic reagents or chemicals. The SurSi peptide is designed capable of not only stabilizing nanoemulsions because of its excellent surface activity, but also inducing the formation of silica through biosilicification at an oil-water interface. However, it remains challenging to precisely control the peptide-induced nucleation and biosilicification specifically at the oil-water interface, thus forming oil-core silica-shell nanocapsules with uniform size and monodispersity. In this study, the fundamental mechanism of silica formation through a peptide catalyzed biosilicification was systematically investigated, so that the formation of oil-core silica-shell nanocapsules can be precisely controlled. The SurSi peptide induced hydrolysis and nucleation of biomineralized silica particles were monitored to study the biosilicification kinetics. Effects of pH, SurSi peptide concentration and pre-hydrolysis of silica precursors were also studied to optimize the formation of biomimetic silica nanocapsules. The fundamental understanding achieved through these systematic studies provides valuable insights for making core-shell nanoparticles via controlling nucleation and reaction at interfaces.