Self-assembled Systems Research Articles

GraphVAMPnets for uncovering slow collective variables of self-assembly dynamics.

Uncovering slow collective variables (CVs) of self-assembly dynamics is important to elucidate its numerous kinetic assembly pathways and drive the design of novel structures for advanced materials through the bottom-up approach. However, identifying the CVs for self-assembly presents several challenges. First, self-assembly systems often consist of identical monomers, and the feature representations should be invariant to permutations and rotational symmetries. Physical coordinates, such as aggregate size, lack high-resolution detail, while common geometric coordinates like pairwise distances are hindered by the permutation and rotational symmetry challenges. Second, self-assembly is usually a downhill process, and the trajectories often suffer from insufficient sampling of backward transitions that correspond to the dissociation of self-assembled structures. Popular dimensionality reduction methods, such as time-structure independent component analysis, impose detailed balance constraints, potentially obscuring the true dynamics of self-assembly. In this work, we employ GraphVAMPnets, which combines graph neural networks with a variational approach for Markovian process (VAMP) theory to identify the slow CVs of the self-assembly processes. First, GraphVAMPnets bears the advantages of graph neural networks, in which the graph embeddings can represent self-assembly structures in high-resolution while being invariant to permutations and rotational symmetries. Second, it is built upon VAMP theory, which studies Markov processes without forcing detailed balance constraints, which addresses the out-of-equilibrium challenge in the self-assembly process. We demonstrate GraphVAMPnets for identifying slow CVs of self-assembly kinetics in two systems: the aggregation of two hydrophobic molecules and the self-assembly of patchy particles. We expect that our GraphVAMPnets can be widely applied to molecular self-assembly.

The Self-Assembly Soluplus Nanomicelles of Nobiletin in Aqueous Medium Based on Solid Dispersion and Their Increased Hepatoprotective Effect on APAP-Induced Acute Liver Injury.

APAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy. The optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo. NOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. These results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.

Micro-simulation insights into the functional and mechanistic understanding of glycyrrhizin against asthma.

Asthma is a common chronic respiratory disease, which causes inflammation and airway stenosis, leading to dyspnea, wheezing and chest tightness. Using transgelin-2 as a target, we virtually screened the lead compound glycyrrhizin from the self-built database of anti-asthma compounds by molecular docking technology, and found that it had anti-inflammatory, anti-oxidative and anti-asthma pharmacological effects. Then, molecular dynamics simulations were used to confirm the stability of the glycyrrhizin-transgelin-2 complex from a dynamic perspective, and the hydrophilic domains of glycyrrhizin was found to have the effect of targeting transgelin-2. Due to the self-assembly properties of glycyrrhizin, we explored the formation process and mechanism of the self-assembly system using self-assembly simulations, and found that hydrogen bonding and hydrophobic interactions were the main driving forces. Because of the synergistic effect of glycyrrhizin and salbutamol in improving asthma, we revealed the mechanism through simulation, and believed that salbutamol adhered to the surface of the glycyrrhizin nano-drug delivery system through hydrogen bonding and hydrophobic interactions, using the targeting effect of the hydrophilic domains of glycyrrhizin to reach the pathological parts and play a synergistic anti-asthmatic role. Finally, we used network pharmacology to predict the molecular mechanisms of glycyrrhizin against asthma, which indicated the direction for its clinical transformation.

Combination therapy to overcome ferroptosis resistance by biomimetic self-assembly nano-prodrug

Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer. Herein, we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib (Gefi), ferrocene (Fc) and dihydroartemisinin (DHA) for the combined therapy of both ferroptosis and apoptosis. In the tumor microenvironment, this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH. Interestingly, the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc, further executing tumor cell death with concomitant chemotherapy by Gefi. More importantly, this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis, as well as no noticeable side-effects during treatments. This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.

Preparation, characterization, and in vivo evaluation of glycyrrhetinic acid-mediated nano-drug delivery system co-loaded with syringopicroside and hydroxytyrosol.

This study aimed to create a glycyrrhetinic acid (GA)-mediated, multi-component, self-assembled nano-drug delivery system co-loaded with syringopicroside (S) and hydroxytyrosol (H) obtained from Syringa Linn by synthesizing a GA-polyethylene glycol-poly (lactic acid-co-glycolic acid) (GPP) nanoparticle delivery carrier to actively target the liver. The nanoparticles were optimized using the central composite design. Nanoparticle characterization, cytotoxicity, pharmacodynamics, and tissue distribution study were performed. The optimized SH-GPP nanoparticle was a white solid powder, which was safe and non-toxic. The particle size and Zeta potential of the nanoparticles were 101.5 ± 3.18nm and -23.3 ± 0.82mV, respectively. The polydispersity index value (PDI) was 0.190 ± 0.005; the particle size distribution was comparatively uniform. The average total encapsulation efficiency of the optimized SH-GPP nanoparticle was 50.26% ± 1.29%, and drug loading was 15.47% ± 0.39%. After S and H were arranged into nanoparticles, the proliferation inhibition of HepG2.2.15 cells was improved, and the aim of drug-loaded synergism between GPP and SH was achieved. The GA-mediated nanoparticles were better targeted, were retained longer in vivo, and had higher concentrations in the liver than the unmodified nanoparticles. These nanoparticles have the potential to be a new effective anti-hepatitis B treatment and have great research potential in clinical treatment.

Gels of Semiconducting Polymers in Benign Solvents.

Gels of semiconducting polymers have many potential applications, including biomedical devices and sensors. Here, we report a self-assembled gel system consisting of isoindigo-based semiconducting polymers with galactose side chains in benign, alcohol-based solvents. Because of the carbohydrate side chains, the modified isoindigo polymers are soluble in alcohols. We obtained thermoreversible gels in 1-propanol using these polymers and di-Fmoc-l-lysine, a molecular gelator. The polymers and molecular gelators have been selected in such a way that they do not have significant physical interactions. The molecular gelator self-assembled to form a fibrous structure that confines the polymer chains in the interstitial spaces of the fibers. The polymer chains formed local aggregations and increased the shear moduli of the gels significantly. Bulky galactose side chains and the less planar nature of the polymer backbone hindered the formation of long-range assembled structures of the polymers. However, the dispersion of polymers throughout the gel samples resulted in a percolated structure in the dried gel films. The bulk electrical conductivity of dried gels confirmed the presence of such percolated structures. Our results demonstrated that carbohydrate-containing conjugated polymers can be combined with molecular gelators to obtain gels in eco-friendly solvents.

Dendrimer-conjugated isotretinoin for controlled transdermal drug delivery

BackgroundIn the present study, we aimed to develop a novel isotretinoin delivery model for treating skin diseases, revealing its potential advantages in drug delivery and targeted therapy.Using a self-assembly strategy, we grafted a dendrimer, based on a well-defined branched structure for nanomedical devices, with a well-defined nanoarchitecture, yielding spherical, highly homogeneous molecules with multiple surface functionalities. Accordingly, a self-assembled dendrimer-conjugated system was developed to achieve the transdermal delivery of isotretinoin (13cRA-D).ResultsHerein, 13cRA-D showed remarkable controlled release, characterized by slow release in normal tissues but accelerated release in tissues with low pH, such as sites of inflammation. These release characteristics could abrogate the nonteratogenic side effects of isotretinoin and allow efficient skin permeation. Moreover, 13cRA-D exhibited high therapeutic efficacy in acne models. Based on in vitro and in vivo experimental results, 13cRA-D afforded better skin penetration than isotretinoin and allowed lesion targeting. Additionally, 13cRA-D induced minimal skin irritation.ConclusionOur findings suggest that 13cRA-D is a safe and effective isotretinoin formulation for treating patients with skin disorders.Graphical

Ultrafast Dynamics of the Medicinal Pigment Curcumin inside the Imidazolium Surface Active Ionic Liquid Containing Giant Vesicles and White Light Generation via Triple-FRET Technique.

The naturally occurring yellow polyphenolic medicinal pigment curcumin shows ultrafast dynamics in the excited states. These ultrafast dynamics are strongly influenced by the rigidity of the environments of the systems. The present investigation unveils the ultrafast excited-state intramolecular hydrogen atom transfer (ESIHT) (which is involved in the antioxidant mechanism) and the solvation dynamics of curcumin inside the imidazolium surface active ionic liquid (SAIL), 1-hexadecyl-3-methylimidazolium chloride ([C16mim]Cl) micelle, and giant vesicles after introducing sorbitan monoesters (Span 20 and Span 80) in the aqueous medium. Interestingly, the short hydrocarbon chain containing Span 20 forms smaller, less rigid vesicles, and the long hydrocarbon chain containing Span 80 forms larger, more rigid giant vesicles after being assembled with [C16mim]Cl. The ESIHT and the solvation dynamics are slower in Span 80, containing rigid vesicles, than that in Span 20, comprising less rigid vesicles. Finally, we have established a three-component fluorescence resonance energy transfer (Triple-FRET) system to generate white light (WL) in the micelle and giant vesicles. Here the hydrophobic dye 1,6-diphenyl-1,3,5-hexatriene (DPH) acts as the donor, and the hydrophilic anticancer drug doxorubicin hydrochloride (DOX) serves as the acceptor along with the intermediate donor, curcumin. At a specific combination of the concentrations of these dyes in a particular self-assembled system, WL is generated due to the triple-FRET phenomena.

DNA droplets for intelligent and dynamical artificial cells: from the viewpoint of computation and non-equilibrium systems.

Living systems are molecular assemblies whose dynamics are maintained by non-equilibrium chemical reactions. To date, artificial cells have been studied from such physical and chemical viewpoints. This review briefly gives a perspective on using DNA droplets in constructing artificial cells. A DNA droplet is a coacervate composed of DNA nanostructures, a novel category of synthetic DNA self-assembled systems. The DNA droplets have programmability in physical properties based on DNA base sequence design. The aspect of DNA as an information molecule allows physical and chemical control of nanostructure formation, molecular assembly and molecular reactions through the design of DNA base pairing. As a result, the construction of artificial cells equipped with non-equilibrium behaviours such as dynamical motions, phase separations, molecular sensing and computation using chemical energy is becoming possible. This review mainly focuses on such dynamical DNA droplets for artificial cell research in terms of computation and non-equilibrium chemical reactions.

Efficient semi-artificial photosynthesis of ethylene by a self-assembled InP-Cyanobacterial biohybrid system.

Biomaufacturing of ethylene is particularly important for modern society. Cyanobacterial cells are able to photosynthesize various valuable chemicals, a promising platform for next-generation biomanufacturing, and semiconductor-cyanobacterial hybrid system are capable of enhancing the solar-to-chemical conversion efficiency. Herein, the native ethylene-producing capability of a filamentous cyanobacterium Nostoc sphaeroides is confirmed experimentally. The self-assembly characteristic of N. sphaeroides is exploited to facilitate its interaction with InP nanomaterial, and the resulted biohybrid system gave rise to further elevated photosynthetic ethylene production. Based on chlorophyll fluorescence measurement and metabolic analysis, the InP nanomaterial augmented photosystem I activity and enhanced ethylene production metabolism of biohybrid cells is confirmed, the mechanism underlying material-cell energy transduction, as well as nanomaterial-modulated photosynthetic light and dark reactions are established. This work not only demonstrated the potential application of semiconductor-N. sphaeroides biohybrid system as a good platform for sustainable ethylene production, but also provided important reference for future studies to construct and optimize nano-cell biohybrid systems for efficient solar-driven valuable chemical production.

DNA-Based Signaling Networks for Transient Colloidal Co-Assemblies.

Programmable chemical circuits inspired by signaling networks in living cells are a promising approach for the development of adaptive and autonomous self-assembling molecular systems and material functions. Progress has been made at the molecular level, but connecting molecular control circuits to self-assembling larger elements such as colloids that enable real-space studies and access to functional materials is sparse and can suffer from kinetic traps, flocculation, or difficult system integration protocols. Herein, we report a toehold-mediated DNA strand displacement reaction network capable of autonomously directing two different microgels into transient and self-regulating co-assemblies. The microgels are functionalized with DNA and become elemental components of the network. The flexibility of the circuit design allows the installation of delay phases or accelerators by chaining additional circuit modules upstream or downstream of the core circuit. The design provides an adaptable and robust route to regulate other building blocks for advanced biomimetic functions.

Detection and Prevention of Unintentional Formation of Loops in Self-Healing Power Systems and Microgrids

Self-healing or self-assembling power systems that rely on local measurements for decision making can provide significant resilience benefits, but they also must include safeguards that prevent the system from self-assembling into an undesirable configuration. One potential undesirable configuration would be the formation of closed loops for which the system was not designed, a situation that can arise any time that two intentional-island systems can be connected in more than one place, e.g. if tie-line breakers are included in the self-assembling system. This paper discusses the unintentional loop formation problem in self-assembling systems and presents a method for mitigating it. This method involves calculating the correlation or the mean absolute error (MAE) between the two local frequency measurements made on either side of a line relay. The correlation and MAE between these frequencies changes significantly between the loop and non-loop cases, and this difference can be used for loop detection. This paper presents and explains the method in detail, presents evidence that the method's underlying assumptions are valid, and demonstrates in PSCAD two implementations of the method. The paper concludes with a discussion of the strengths and weaknesses of the proposed method.

Complexes and Supramolecular Associates of Dodecyl-Containing Oligonucleotides with Serum Albumin.

Serum albumin is currently in the focus of biomedical research as a promising platform for the creation of multicomponent self-assembling systems due to the presence of several sites with high binding affinity of various compounds in its molecule, including lipophilic oligonucleotide conjugates. In this work, we investigated the stoichiometry of the dodecyl-containing oligonucleotides binding to bovine and human serum albumins using an electrophoretic mobility shift assay. The results indicate the formation of the albumin-oligonucleotide complexes with a stoichiometry of about 1 : (1.25 ± 0.25) under physiological-like conditions. Using atomic force microscopy, it was found that the interaction of human serum albumin with the duplex of complementary dodecyl-containing oligonucleotides resulted in the formation of circular associates with a diameter of 165.5 ± 94.3 nm and 28.9 ± 16.9 nm in height, and interaction with polydeoxyadenylic acid and dodecyl-containing oligothymidylate resulted in formation of supramolecular associates with the size of about 315.4 ± 70.9 and 188.3 ± 43.7 nm, respectively. The obtained data allow considering the dodecyl-containing oligonucleotides and albumin as potential components of the designed self-assembling systems for solving problems of molecular biology, biomedicine, and development of unique theranostics with targeted action.

Peptide-Based Optical/Electronic Materials: Assembly and Recent Applications in Biomedicine, Sensing, and Energy Storage.

The unique optical and electronic properties of living systems are impressive. Peptide-based supramolecular self-assembly systems attempt to mimic these properties by preparation optical/electronic function materials with specific structure through simple building blocks, rational molecular design, and specific kinetic stimulation. From the perspective of building blocks and assembly strategies, the unique optical and electronic properties of peptide-based nanostructures, including peptides self-assembly and peptides regulate the assembly of external function subunits, are systematically reviewed. Additionally, their applications in biomedicine, sensing, and energy storage are also highlighted. This bioinspired peptide-based function material is one of the hot candidates for the new generation of green intellect materials, with many advantages such as biocompatibility, environmental friendliness, and adjustable morphology.

Cancer Stem-like Cells-Oriented Surface Self-Assembly to Conquer Radioresistance.

Cancer stem-like cells (CSCs), capable of indefinite self-renewal and differentiation, are considered to be the root cause of tumor radiotherapy (RT) resistance. However, the CSCs-targeted therapy still remains to be a great challenge because they are commonly located in the deep tumor making drugs hard to approach, and their hypoxic and acidic niche can further aggravate radioresistance. Herein, based on our finding that hypoxic CSCs highly express carbonic anhydrase IX (CAIX) on the cell membrane, a CAIX-targeted induced in situ self-assembly system on the surface of CSC is reported to overcome hypoxic CSC-mediated radioresistance. Via the sequential processes of "monomer release-target accumulation-surface self-assembly," the constructed peptide-based drug delivery system (CA-Pt) exhibits the advantages of deep penetration, amplified CAIX inhibition, and enhanced cellular uptake, which greatly relieves the hypoxic and acidic microenvironment to promote the hypoxic CSC differentiation and combines with platinum to boost the RT-inducing DNA damage. In both lung cancer tumor mouse and zebrafish embryo models, CA-Pt treatment can effectively assist RT in suppressing tumor growth and preventing tumor invasion and metastasis. This study used a surface-induced self-assembly strategy to differentiate hypoxic CSCs, which may provide a universal treatment strategy for overcoming tumor radioresistance. This article is protected by copyright. All rights reserved.

Review of self-assembly of nanoparticles and its applications in the manufacturing of different types of colloids

An innovative approach that blends nanotechnology technologies with supramolecular chemistry can accelerate the creation of complex nanoparticle-based goods, self-assembly is used in the production of nanoscale self-assembled systems with desired properties with great versatility and potential. One of the most intriguing classes of material that can be constructed by self-assembly is colloids which is widely used in many areas, especially in the pharmaceutical and industry.

An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy.

The acidosis anti-tumor therapy, based on the altered energy metabolism pathway of tumor cells, has been proposed as an attractive method for cancer selective treatment. However, the strategy of inducing tumor acidosis by using a single drug to simultaneously inhibit both lactate efflux and consumption has not been reported yet. Herein, an in situ enzyme-instructed self-assembly (EISA) system was rationally fabricated to induce tumor acidosis apoptosis for cancer selective therapy. Depending on the sequential effect of the in situ EISA system, the targeted drug was successively distributed on the membrane and intracellular, inhibiting MCT4 mediated lactate efflux and mitochondrial tricarboxylic acid (TCA) cycle mediated lactate consumption, respectively. Through the dual obstruction of lactate metabolism to trigger tumor acidosis, the in situ EISA nanomedicine showed selective growth and migration inhibition against cancer cells. In addition, the nanomedicine also displayed a radio-sensitization effect in vitro due to causing the mitochondrial dysfunction, and exhibited a prominent synergistic chemo-radiotherapy anti-tumor performance in vivo. Accordingly, this work demonstrated that the in situ EISA system could endow the LND with sequential-dual effects to induce tumor acidosis, which may provide an enlightening strategy for anticancer drug delivery and cancer selective therapy. STATEMENT OF SIGNIFICANCE: With the help of the sequential effect of in situ EISA , the serial attack of LND against different targets was effectively realized to induce tumor acidosis and combined chemo-radiotherapy, implying the importance of the relationship between structure and function, which could offer a distinctive inspiration for future drug delivery system design and anti-tumor application.

How hydrophobicity shapes the architecture of protein assemblies

The interactions that give rise to protein self-assembly are basically electrical and hydrophobic in origin. The electrical interactions are approached in this study as the interaction between electrostatic dipoles originated by the asymmetric distribution of their charged amino acids. However, hydrophobicity is not easily derivable from basic physicochemical principles. Its treatment is carried out here considering a hydrophobic force field originated by “hydrophobic charges”. These charges are indices obtained experimentally from the free energies of transferring amino acids from polar to hydrophobic media. Hydrophobic dipole moments are used here in a manner analogous to electric dipole moments, and an empirical expression of interaction energy between hydrophobic dipoles is derived. This methodology is used with two examples of self-assembly systems of different complexity. It was found that the hydrophobic dipole moments of proteins tend to interact in such a way that they align parallel to each other in a completely analogous way to how phospholipids are oriented in biological membranes to form the well-known double layer. In this biological membrane model (BM model), proteins tend to interact in a similar way, although in this case this alignment is modulated by the tendency of the corresponding electrostatic dipoles to counter-align.Graphical abstractHelical conformation of influenza virus PDBid: 6Z5L. Two monomers are shown in cyan and green. The corresponding dipole moment vectors are shown in red (electric dipoles) and blue (hydrophobic dipoles). From the inset figure, it can be seen that the growth of the helix is due to electrical attraction of the monomers, overcoming a hydrophobic repulsion (see text)

New Trends in 4D Printing: A Critical Review

In a variety of industries, Additive Manufacturing has revolutionized the whole design–fabrication cycle. Traditional 3D printing is typically employed to produce static components, which are not able to fulfill dynamic structural requirements and are inappropriate for applications such as soft grippers, self-assembly systems, and smart actuators. To address this limitation, an innovative technology has emerged, known as “4D printing”. It processes smart materials by using 3D printing for fabricating smart structures that can be reconfigured by applying different inputs, such as heat, humidity, magnetism, electricity, light, etc. At present, 4D printing is still a growing technology, and it presents numerous challenges regarding materials, design, simulation, fabrication processes, applied strategies, and reversibility. In this work a critical review of 4D printing technologies, materials, and applications is provided.

Synthetic molecular motor activates drug delivery from polymersomes.

The design of stimuli-responsive systems in nanomedicine arises from the challenges associated with the unsolved needs of current molecular drug delivery. Here, we present a delivery system with high spatiotemporal control and tunable release profiles. The design is based on the combination of an hydrophobic synthetic molecular rotary motor and a PDMS-b-PMOXA diblock copolymer to create a responsive self-assembled system. The successful incorporation and selective activation by low-power visible light (λ = 430 nm, 6.9 mW) allowed to trigger the delivery of a fluorescent dye with high efficiencies (up to 75%). Moreover, we proved the ability to turn on and off the responsive behavior on demand over sequential cycles. Low concentrations of photoresponsive units (down to 1 mol% of molecular motor) are shown to effectively promote release. Our system was also tested under relevant physiological conditions using a lung cancer cell line and the encapsulation of an Food and Drug Administration (FDA)-approved drug. Similar levels of cell viability are observed compared to the free given drug showing the potential of our platform to deliver functional drugs on request with high efficiency. This work provides an important step for the application of synthetic molecular machines in the next generation of smart delivery systems.