Self-assembly Mechanism Research Articles

A coarse-grained simulation model for colloidal self-assembly via explicit mobile binders.

Colloidal particles with mobile binding molecules constitute a powerful platform for probing the physics of self-assembly. Binding molecules are free to diffuse and rearrange on the surface, giving rise to spontaneous control over the number of droplet-droplet bonds, i.e., valence, as a function of the concentration of binders. This type of valence control has been realized experimentally by tuning the interaction strength between DNA-coated emulsion droplets. Optimizing for valence two yields droplet polymer chains, termed 'colloidomers', which have recently been used to probe the physics of folding. To understand the underlying self-assembly mechanisms, here we present a coarse-grained molecular dynamics (CGMD) model to study the self-assembly of this class of systems using explicit representations of mobile binding sites. We explore how valence of assembled structures can be tuned through kinetic control in the strong binding limit. More specifically, we optimize experimental control parameters to obtain the highest yield of long linear colloidomer chains. Subsequently tuning the dynamics of binding and unbinding via a temperature-dependent model allows us to observe a heptamer chain collapse into all possible rigid structures, in good agreement with recent folding experiments. Our CGMD platform and dynamic bonding model (implemented as an open-source custom plugin to HOOMD-Blue) reveal the molecular features governing the binding patch size and valence control, and opens the study of pathways in colloidomer folding. This model can therefore guide programmable design in experiments.

Optimisation of GraPhage13 macro-dispersibility via understanding the pH-dependent ionisation during self-assembly: towards the manufacture of graphene-based nanodevices.

GraPhage13 aerogels (GPAs) are micro-porous structures generated through the self-assembly of graphene oxide (GO) and M13 bacteriophage. As GPA fabrication involves the aggregation of GO and M13 in aqueous solution, we aim to understand its dispersibility across a wide pH range. Herein, a novel technique has been developed to relate the ionisation of functional groups to the surface charge, offering insights into the conditions required for GPA fabrication and the mechanism behind its self-assembly. The aggregation of GO and M13 was observed between pH 2-6 and exhibited dependence on the surface charge of the resulting aggregate with the M13 bacteriophage identified as the primary factor contributing to this, whilst originating from the ionisation of its functional groups. In contrast, GO exhibited a lesser impact on the surface charge due to the deprotonation of its carboxylic, enolic and phenolic functional groups at pH 6 and above, which falls outside the required pH range for aggregation. These results enhance our understanding of the GPA self-assembly mechanism, the conditions required for their fabrication and the optimal processability, laying the foundation towards its broad range of applications and the subsequent manufacture of graphene-based nanodevices.

Facile one-pot synthesis of polyethyleneimine functionalized α-FeOOH nanoraft consisted of single-layer parallel-aligned ultrathin nanowires for efficient removal of Cr (VI): Synergy of reduction and adsorption

Two-dimensional (2D) iron oxide-hydroxide (FeOOH) nanomaterials as low-cost and environmental-friendly composites are promising materials for application in heavy metal elimination. However, developing 2D FeOOH adsorbents with high adsorption capacity and excellent durability toward Cr (VI) removal is still a challenge due to the intrinsically non-layered structure. Here, a novel polyethyleneimine (PEI) functionalized 2D single-layer nano-raft-like α-FeOOH (α-FeOOH NF) consisted of parallel-aligned ultrathin nanowires was obtained via a facile one-pot hydrothermal approach. It was found that the 2D α-FeOOH NF nanostructure was formed by an in-plane iterative self-assembly mechanism, where α-FeOOH nanoparticles acted as intermediates and iterative seeds with anisotropic growth. The as-prepared 2D α-FeOOH NF possessed porous structure and high surface area, which provided a strong ability to capture the Cr (VI) ions in water. Benefiting from the unique structure and PEI modification, it exhibited fast adsorption kinetic rate, high reusability, and high adsorption capacity toward Cr(VI) removal. The removal mechanism involved adsorption and reduction process. Besides, the molecular dynamic simulations disclosed a facet-dependent Cr(VI) adsorption behavior of α-FeOOH. The maximum adsorption capacity was 67.1 mg/g and the removal efficiency still maintained 83.9 % in the fifth cycle. This work demonstrated that 2D α-FeOOH NF could be a promising adsorbent for Cr(VI) removal.

Assembly of Helical Nanostructures: Solvent-Induced Morphology Transition and Its Effect on Cell Adhesion.

Being able to precisely manipulate both the morphology and chiroptical signals of supramolecular assemblies will help to better understand the natural biological self-assembly mechanism. Two simple l/d-phenylalanine-based derivatives (L/DPFM) have been designed, and their solvent-dependent morphology evolutions are illustrated. It was found that, as the content of H2 O in aqueous ethanol solutions was increased, LPFM self-assembles first into right-handed nanofibers, then flat fibrous structures, and finally inversed left-handed nanofibers. Assemblies in ethanol and H2 O exhibit opposite conformations and circular dichroism (CD) signals even though they are constructed from the same molecules. Thus, the morphology-dependent cell adhesion and proliferation behaviors are further characterized. Left-handed nanofibers are found to be more favorable for cell adhesion than right-handed nanostructures. Quantitative AFM analysis showed that the L929 cell adhesion force on left-handed LPFM fibers is much higher than that on structures with inversed handedness. Moreover, the value of cell Young's modulus is lower for left-handed nanofibrous films, which indicates better flexibility. The difference in cell-substrate interactions might lead to different effects on cell behavior.

Unraveling the mechanism of the supramolecular self-assembly during the in vivo metabolism of geniposide from Chinese medicine

Unraveling the detailed mechanism of Chinese medicine in curing diseases is of vital importance for the development of such long-standing traditional medicine. Here, we investigated the exposed form in vivo and bioactivity of Chinese medicine from an aspect of supramolecular chemistry. We demonstrated that the genipin (GP), an aglycone of geniposide (GE) transformed by β-glucosidase, can react with methylamine (MA), a harmful metabolite in the gut, to produce gardenia blue in vivo, which leads to a significant decrease of MA. The gardenia blue is supramolecular assemblies (SA), which can alleviate the interference with intestinal bacteria. Moreover, the formation mechanism of SA was revealed, in which genimethylamine reacted from GP and MA, was covalently polymerized into dimers and then non-covalently self-assembled into the SA. This study provides evidence that the supramolecular pigments can be formed in vivo during the metabolism of Chinese medicine through simultaneously covalent and non-covalent assembly, which may play key roles in their pharmacological activity.

Engineered Self-Assembly of Amphiphilic Cyclodextrin Conjugates for Drug Encapsulation.

Cyclodextrins are a group of naturally occurring oligosaccharides that have widely been studied and applied in pharmaceutical formulations forming inclusion complexes with a broad variety of drugs exhibiting different hydrophilicity as well as molecular weights. Grafting aliphatic chains onto native cyclodextrins renders them amphiphilic and enables self-assembly into supramolecular structures that have already been explored for drug delivery. Based on the possibility of controlling the inherent physicochemical properties by modifying their chemical structure, amphiphilic cyclodextrin conjugates hold a great potential to become a drug delivery platform adaptable to the individual needs of specific active drug molecules. In this work, a library of amphiphilic cyclodextrin derivatives was synthesized by conjugating aliphatic chains of different lengths to native β-cyclodextrin via thioether or ester bonds. Upon nanoprecipitation, the synthesized amphiphilic cyclodextrin derivatives spontaneously self-assembled into nanosized supramolecular structures with a monodisperse size distribution. We systematically investigated the relationship between the molecular structure of the amphiphilic cyclodextrin derivatives and the corresponding self-assembly into nanosystems as well as the encapsulation of model drugs with different physicochemical properties. Encapsulation efficiencies up to 97% and pH-dependent release profiles were achieved. We found that both the aliphatic chain length and the linker molecule determine the respective self-assembly and drug encapsulation mechanism of the individual system. The colloidal stability and biocompatibility with human cells of all derivatives were proven. Consequently, amphiphilic cyclodextrin conjugates provide a drug delivery platform with tailor-made control over physicochemical properties and high drug encapsulation efficiency for a broad range of drug molecules, thus offering great potential for the development of future therapeutics with improved therapeutic efficiency.

Molecular self-assembling structure and formation mechanism of lubricating grease: A computational simulation approach

Grease is an important type of lubricant. In this study, a computational simulation strategy suitable for revealing the self-assembled structure of grease and its formation mechanism is investigated by combining the advantages of quantum mechanics, molecular dynamics, and dissipative particle dynamics. The results show that the main driving force of self-assembly of thickener molecules in oil is electrostatic force; the molecular configuration of the thickener changes from a bending to a stretching state during the cooling process. The simulation methods developed in this work are successfully applied to study the formation mechanism of sodium stearate and potassium stearate grease, and the results are in good agreement with the experimental results.

From polyethyleneimine hydrogels to Pickering-like smart “On/Off” emulgels switched by pH and temperature

According to the so-called colloidal tectonic concept, we assumed that a single self-complementary polymer-based tecton could be used to design self-assembled emulsions. The polymer must be of high-molecular weight with balanced bipolar properties generating those of rigidity and flexibility. Linear polyethyleneimine (LPEI, 25kDa) was used because it acts as a buffer by continuous protonation/deprotonation of the amine groups. The relationships between the physicochemical properties of LPEI (protonation, charge, size, aggregation and gelation) and emulsions (type, droplet size, rheological behavior and stability) were investigated to highlight the self-assembly and stabilization mechanisms during the construction events as well as the inherent properties of emulsions (responsiveness to external stimuli). In aqueous solution, after a first heat and cool cycle, the adequate and spontaneous self-assembly of hydrophobic and hydrophilic sections leads to hydrogels by the formation of a 3D network where the crystallized hydrophobic domains act as knots. In the presence of various oils, the hydrogels provide long-term stable Pickering emulgels. The as-prepared emulsions are highly controllable due to their self-assembled nature (up to 10 consecutive runs). Consequently, this new approach provides a facile route to construct self-assembled, reversible and dynamics Pickering-like emulsions by simplifying the colloidal tectonics concept.

Microstructured three-dimensional disc-like CuCo2O4/CuO composite derived from a self-assembly mechanism for high-performance battery-type supercapacitors

In this work, a one-step solvothermal technique was used to produce CuCo2O4/CuO composite. The composites have a high surface area of 45.36 m2 g−1, and a 16.41 nm pore size. The composite with mesoporous structures is suitable for fast faradaic reactions because it can ensure enough interaction between the electrolyte and electrode, and those ions and electrons can move quickly. In the backdrop of the supercapacitors, the composite electrode showed the typical features of battery-type characteristics and exhibited a high specific capacity of 458 C g−1 at the current density of 1 A g−1. In addition, the composite electrode exhibited better rate capability (60% of its initial value at 10 A g−1) and 10% capacity loss after 8000 cycles at 7 A g−1. In this context, CuCo2O4/CuO composite has excellent electrochemical properties, making it an ideal electrode material for supercapacitors.

Self-Assembling Peptide-Based Functional Biomaterials.

Peptides can self-assemble into various hierarchical nanostructures through noncovalent interactions and form functional materials exhibiting excellent chemical and physical properties, which have broad applications in bio-/nanotechnology. The self-assembly mechanism, self-assembly morphology of peptide supramolecular architecture and their various applications, have been widely explored which have the merit of biocompatibility, easy preparation, and controllable functionality. Herein, we introduce the latest research progress of self-assembling peptide-based nanomaterials and review their applications in biomedicine and optoelectronics, including tissue engineering, anticancer therapy, biomimetic catalysis, energy harvesting. We believe that this review will inspire the rational design and development of novel peptide-based functional bio-inspired materials in the future.

Ultra-fast dynamic deposition of EuBa2Cu3O7−δ-BaHfO3 nanocomposite films: Self-assembly structure modulation and flux pinning behaviors

Structure modulation of rare-earth barium cuperates (REBCO) superconducting films plays an essential role in the flux pinning behaviors. In this paper, nano-composite EuBa2Cu3O7−δ-BaHfO3 (EuBCO/BHO) films were deposited by the ultra-fast pulsed laser deposition technique. All nano-composite films exhibited high-quality orientation under the growth rates up to 100 nm/s. TEM cross-sectional analysis reveals that the EuBCO/BHO films have a distinct lamellar structure, which is related to the periodic change of growth conditions during the multi-turn dynamic deposition. In addition, the morphology of BHO varies with dopant content, which suggests a strong correlation between dopant content and the BHO self-assembly mechanism. Consequently, the vortex behavior shifts from giant-flux creep to vortex-glass formation at the thermally activated flux flow region as the dopant content increases. The primary flux pinning behaviors change from random to correlated pinning with the increase of dopant content at 4.2 K. Due to the larger contribution of the correlated pinning machinimas, the 8% BHO-doped EuBCO film exhibits the highest Jc value at 4.2 K, with moderate fields (below 8 T) among all the three films. At 4.2 K and 14 T, the 6% BHO doped EuBCO film has the highest Fp value attributing to the predominate random pinning mechanism.

Controlled Supramolecular Self-Assembly Pathways by Intramolecular Rotation of D-A Molecular System toward the Signal Differentiation Detection of Toxic Vapors.

Revealing the structural evolution mechanisms of supramolecular self-assembly can facilitate the exploitation of new self-assembly pathways and various functional materials. Here, this work reports a unique intramolecular rotation-induced structural evolution of supramolecular assemblies from a metastable state to a thermodynamically stable state using a twisting D-A molecule. These self-assemblies are applied to the signal differentiation detection of toxic dimethylsulfide (DMS) vapors. The F161 BT monomer of the inactive state is trapped in off-pathway metastable nanospheres, which can disassemble and induce the transformation of the F161 BT monomer into an active state by crossing the energy barrier. Subsequently, the active monomer goes through the processes of nucleation and elongation, forming thermodynamically stable on-pathway microribbons. Adding seeds can accelerate the molecular conformational transformation, generating microribbons with controlled lengths. Opposite fluorescent responses are obtained when exposing the two aggregates to the DMS vapors, allowing the sensitive detection of DMS with enhanced selectivity, which offers tremendous potential in practical applications.

The gel mechanism and carrier quality of fibrous and granular whey protein self-assembly

In this study, we induced a 6% protein concentration of whey protein (WP) to form fibrous and granular whey protein self-assembly (FWS and GWS respectively) by a pH-temperature gradient. The fibrous and granular whey protein self-assembly were used as raw material to explore the mechanism of gel formation and their potential a new delivery system loaded with Epigallocatechin gallate (EGCG) was evaluated. Compared with native WP, the α-helix decreased, and the β-sheet increased in FWS, while the opposite was found in GWS. The hydrophobic interaction played a crucial role in the formation process of FWS and GWS, while disulfide bonds played a slightly more vital role in the formation process of GWS. The gels prepared by FWS and GWS had denser microstructure and stronger mechanical strength than native WP gel. Both the water holding capacity and hardness of the gels prepared by FWS and GWS were significantly higher than those prepared by native WP. The water holding capacity of the gel prepared by FWS was higher than that of the gel prepared by GWS at the same protein concentration, but the hardness results were the opposite. Hydrophobic interaction and hydrogen bonds played a dominant role during the gel formation process of FWS and GWS, while disulfide bonds only played a role in the gel formation process of GWS. In addition, the gel formed by FWS and GWS had higher epigallocatechin gallate encapsulation efficiency (94.40% and 95.09%, respectively) and a slow control effect during digestion. Therefore, gel prepared by FWS and GWS can provide essential ideas for building new protein gel technology and is expected to be an ideal carrier for bioactive substances.

Study on the configuration isomerism of [V6B20O50]16− cluster cage

Two novel vanadoborates were synthesized under hydrothermal conditions with different conformations (eclipsed and staggered) Li5[V6B20O39(OH)11]·8H2O 1 and (enH)2(enH2)2Cs2[V6B20O42(OH)8(H2O)0.5]·3H2O 2 (en = ethylenediamine) and analyzed by single crystal X-ray diffraction, powder X-ray diffraction (PXRD) analysis, two-dimensional infrared correlation spectroscopy (2D-IR COS) Characterization and density functional theory calculations. The cluster anion of both compounds is [V6B20O50]16−, which is a sandwich structure composed of a V6 ring and two [B10O16] triangles. In compound 2, the two [B10O16] triangles of the [V6B20O50] 16−cluster anion are staggered by 60 degrees, forming an isomer configurationally different from compound 1. The similarities and differences between the 2D-IR COS spectra of the two compounds are explained from the structural point of view. Theoretical calculation shows that two staggered cluster anions have similar in energies and thus should be able to coexist. This study not only fills the gap in the study of the isomer of vanadoborates, but also makes an outstanding contribution to the study of the self-assembly mechanism of polyoxometalates.

Self-assembly of cellulose nanocrystals of different lengths

HypothesisThe self-assembly (SA) of cellulose nanocrystals (CNC) in suspensions is important both from the fundamental and advanced technology development perspective. CNC of different lengths self-assemble differently in suspensions by balancing attractive and repulsive interactions which depends strongly on morphology, surface chemistry and concentrations.ExperimentsTwo different commercial CNC samples (CNC-M and CNC-C) of different lengths were dispersed in Milli-Q water at different concentrations (0.5–10 wt%). CNC-M is provided as a gel at a solid concentration of 10.3 wt% which was diluted in Milli-Q water. CNC-C is sold as a powder which was dispersed in Milli-Q water with a mixer to achieve the desired concentrations. TEM was used to determine morphology of CNC. Polarised optical microscopy is performed to get microscale visualisation of the chiral nematic self-assembly. High flux synchrotron SAXS is applied to evaluate and compare the nanoscale self-assembly mechanisms of CNC of different lengths.FindingsThe SA of two different types of CNC rods of similar diameter but different lengths is investigated. SAXS analysis shows the short rods in suspension form an isotropic phase (randomly oriented) at lower concentration (0–4 wt%); as concentration is increased, the rods become systematically aligned in a nematic phase. The interrod distance d varies as c−0.33 at the lower concentration, which changes to c−0.5 and even c−1 at the higher concentrations. In contrast, the long rods in suspension remain in the isotropic phase throughout the measured concentration range from 0.5 to 10 wt%. The interrod distance also follows the isotropic power law slope of c−0.33. Suspensions made of the short CNC rods show long range order and large interrod distance compared to those formed by the long rods. POM agrees with the SAXS results. A specific equilibrium between attractive and repulsive forces is required to maintain SA and ordering of the rods. DLVO calculations reveal that the long rods maintain van der Waal attractive force dominating over the electrostatic repulsion, which hinders rods alignment in an ordered manner. However, for the short rods, the weaker attractive interactions are well compensated by the repulsive force which aligns rods in an ordered assembly. This fundamental understanding of the SA of rods in suspensions facilitates the engineering of novel CNC composites of unique optical properties which enables novel applications such as in sensors and bio-diagnostics.

Molecular Insights into the Misfolding and Dimerization Dynamics of the Full-Length α-Synuclein from Atomistic Discrete Molecular Dynamics Simulations.

The misfolding and pathological aggregation of α-synuclein forming insoluble amyloid deposits is associated with Parkinson's disease, the second most common neurodegenerative disease in the world population. Characterizing the self-assembly mechanism of α-synuclein is critical for discovering treatments against synucleinopathies. The intrinsically disordered property, high degrees of freedom, and macroscopic timescales of conformational conversion make its characterization extremely challenging in vitro and in silico. Here, we systematically investigated the dynamics of monomer misfolding and dimerization of the full-length α-synuclein using atomistic discrete molecular dynamics simulations. Our results suggested that both α-synuclein monomers and dimers mainly adopted unstructured formations with partial helices around the N-terminus (residues 8-32) and various β-sheets spanning the residues 35-56 (N-terminal tail) and residues 61-95 (NAC region). The C-terminus mostly assumed an unstructured formation wrapping around the lateral surface and the elongation edge of the β-sheet core formed by an N-terminal tail and NAC regions. Dimerization enhanced the β-sheet formation along with a decrease in the unstructured content. The inter-peptide β-sheets were mainly formed by the N-terminal tail and NACore (residues 68-78) regions, suggesting that these two regions played critical roles in the amyloid aggregation of α-synuclein. Interactions of the C-terminus with the N-terminal tail and the NAC region were significantly suppressed in the α-synuclein dimer, indicating that the interaction of the C-terminus with the N-terminal tail and NAC regions could prevent α-synuclein aggregation. These results on the structural ensembles and early aggregation dynamics of α-synuclein will help understand the nucleation and fibrillization of α-synuclein.

Turning a polystyrene microsphere into a multimode light source by laser irradiation

Abstract Polystyrene (PS) is generally considered as a passive optical material that is transparent to light with wavelengths longer than 300 nm. In practice, PS micro- and nanospheres with uniform sizes are usually used to build photonic crystals based on self-assembly mechanism. Here, we demonstrate experimentally that PS microspheres supporting whispery gallery modes can be transformed into multimode light sources by laser irradiation. We show that a PS microsphere placed on a silica substrate can be lighted up when it is consecutively irradiated by using a 488-nm continuous wave laser beam with a pumping power above a threshold. Broadband luminescence emitted from the PS microsphere increases rapidly to a maximum value and decreases gradually with increasing irradiation time, implying the generation and degradation of a certain luminescent material upon laser irradiation. However, the PS microsphere is found to be damaged by high temperature based on morphology examination. By replacing the silica substrate with a thin silver film, the threshold laser power for lighting up a PS microsphere is dramatically reduced. More importantly, we can see enhanced luminescence intensities from the whispery gallery modes supported by the PS microsphere, which becomes an efficient multimode light source. Interestingly, the threshold laser power can be further lowered by inserting a molybdenum disulfide monolayer in between the PS microsphere and the silver film. As a result, the PS microsphere remains nearly unchanged except the formation of the luminescence material. Our findings open a new horizon for the interaction of polymer with laser light by exploiting the optical resonances supported by micro- and nanoparticles and pave the way for constructing photonic devices based on laser-induced luminescent materials in polymers.

Fabrication Mechanisms of Lignin Nanoparticles and Their Ultraviolet Protection Ability in PVA Composite Film.

Lignin is an indispensable and essential compound present in plants. It is a renewable resource and a green alternative to traditional petroleum energy. The rational utilization of lignin can reduce the environmental damage caused by traditional industrial development. The preparation of lignin nanoparticles (LNPs) using the self-assembly method is one of the most favorable ways to achieve high value-added utilization of lignin. However, the process requires an in-depth understanding of the sphere-forming mechanism of lignin self-assembly and the interaction of self-assembly forces. We used the same raw materials and two different preparation methods to prepare LNPs. The results revealed that the variation in the order of the dropwise addition of lignin solution and deionized water produced LNPs with varying average sizes. The sphere-forming mechanisms of the two kinds of lignin nanoparticles were discussed for the preparation of UV-resistant polyvinyl alcohol (PVA) polymeric films. During lignin spherification, the faster the solution reaches the supersaturation state, the faster the spherogenesis rate is, the smaller the size is, and the narrower the particle size distribution is. The lignin micro/nanospheres are produced by exploiting the π–π bonding interactions in lignin itself. The lignin micro/nanospheres are then mixed with PVA to form a film to obtain a lignin–PVA composite film material with an anti-UV effect.

Contribution of the 12-17 hydrophobic region of islet amyloid polypeptide in self-assembly and cytotoxicity.

The islet amyloid polypeptide (IAPP) is a 37-residue aggregation-prone peptide hormone whose deposition as insoluble fibrils in the islets of Langerhans is associated with type II diabetes. Therapeutic interventions targeting IAPP amyloidogenesis, which contributes to pancreatic β-cell degeneration, remain elusive owing to the lack of understanding of the self-assembly mechanisms and of the quaternary proteospecies mediating toxicity. While countless studies have investigated the contributions of the 20–29 amyloidogenic core in self-assembly, IAPP central region, i.e. positions 11 to 19, has been less studied, notwithstanding its potential key role in oligomerization. In this context, the present study aimed at investigating the physicochemical and conformational properties driving IAPP self-assembly and associated cytotoxicity. Computational tools and all-atom molecular dynamics simulation suggested that the hydrophobic 12–17 segment promotes IAPP self-recognition and aggregation. Alanine scanning revealed that the hydrophobic side chains of Leu12, Phe15 and Val17 are critical for amyloid fibril formation. Destabilization of the α-helical folding by Pro substitution enhanced self-assembly when the pyrrolidine ring was successively introduced at positions Ala13, Asn14 and Phe15, in comparison to respective Ala-substituted counterparts. Modulating the peptide backbone flexibility at position Leu16 through successive incorporation of Pro, Gly and α-methylalanine, inhibited amyloid formation and reduced cytotoxicity, while the isobutyl side chain of Leu16 was not critical for self-assembly and IAPP-mediated toxicity. These results highlight the importance of the 12–17 hydrophobic region of IAPP for self-recognition, ultimately supporting the development of therapeutic approaches to prevent oligomerization and/or fibrillization.

Self-assembly hydrogels of therapeutic agents for local drug delivery.

Advanced drug delivery systems are of vital importance to enhance therapeutic efficacy. Among various recently developed formulations, self-assembling hydrogels composed of therapeutic agents have shown promising potential for local drug delivery owing to their excellent biocompatibility, high drug-loading efficiency, low systemic toxicity, and sustained drug release behavior. In particular, therapeutic agents self-assembling hydrogels with well-defined nanostructures are beneficial for direct delivery to the target site via injection, not only improving drug availability, but also extending their retention time and promoting cellular uptake. In brief, the self-assembly approach offers better opportunities to improve the precision of pharmaceutical treatment and achieve superior treatment efficacies. In this review, we intend to cover the recent developments in therapeutic agent self-assembling hydrogels. First, the molecular structures, self-assembly mechanisms, and application of self-assembling hydrogels are systematically outlined. Then, we summarize the various self-assembly strategies, including the single therapeutic agent, metal-coordination, enzyme-instruction, and co-assembly of multiple therapeutic agents. Finally, the potential challenges and future perspectives are discussed. We hope that this review will provide useful insights into the design and preparation of therapeutic agent self-assembling hydrogels.