Confined space design by nanoparticle self-assembly

Nanoparticle (NP) self-assembly has led to the fabrication of an array of functional nanoscale systems, having diverse architectures and functionalities. In this perspective, we discuss the design and application of NP suprastructures (SPs) characterized by nanoconfined compartments in their self-assembled framework, providing an overview about SP synthetic strategies reported to date and the role of their confined nanocavities in applications in several high-end fields. We also set to give our contribution towards the formation of more advanced nanocompartmentalized SPs able to work in dynamic manners, discussing the opportunities of further advances in NP self-assembly and SP research.

This perspective gives an outlook on the design of interparticle confined nanocavities in self-assembled NP systems and their functional relevance.     

Directional asymmetry over multiple length scales in reticular porous materials

In nature and synthetic materials, asymmetry is a useful tool to create complex and functional systems constructed from a limited number of building blocks. Reticular chemistry has allowed the synthesis of a wide range of discrete and extended structures, from which modularity permits the controlled assembly of their constituents to generate asymmetric configurations of pores or architectures. In this perspective, we present the different strategies to impart directional asymmetry over nano/meso/macroscopic length scales in porous materials and the resulting novel properties and applications.

Design strategies for the controlled assembly of discrete and extended reticular materials with asymmetric configurations of pores or architectures.     

Metallohelices emulate the properties of short cationic α-helical peptides

Naturally occurring peptides in many living systems perform antimicrobial and anticancer host defence roles, but their potential for clinical application is limited by low metabolic stability and relatively high costs of goods. Self-assembled helical metal complexes provide an attractive synthetic platform for non-peptidic architectures that can emulate some of the properties of short cationic α-helical peptides, with tuneable charge, shape, size and amphipathicity. Correspondingly there is a growing body of evidence demonstrating that these supramolecular architectures exhibit bioactivity that emulates that of the natural systems. We review that evidence in the context of synthetic advances in the area, driven by the potential for biomedical applications. We note some design considerations for new biologically-relevant metallohelices, and give our outlook on the future of these compounds as therapeutic peptidomimetics.

Advances in metal–organic self-assembly have unearthed an area of chemical space containing peptide-emulating molecules. Comparison with natural systems indicates future directions in terms of synthesis, disease areas and mechanistic understanding.     

Nucleation mechanisms and speciation of metal oxide clusters

The self-assembly mechanisms of polyoxometalates (POMs) are still a matter of discussion owing to the difficult task of identifying all the chemical species and reactions involved. We present a new computational methodology that identifies the reaction mechanism for the formation of metal-oxide clusters and provides a speciation model from first-principles and in an automated manner. As a first example, we apply our method to the formation of octamolybdate. In our model, we include variables such as pH, temperature and ionic force because they have a determining effect on driving the reaction to a specific product. Making use of graphs, we set up and solved 2.8 × 10⁵ multi-species chemical equilibrium (MSCE) non-linear equations and found which set of reactions fitted best with the experimental data available. The agreement between computed and experimental speciation diagrams is excellent. Furthermore, we discovered a strong linear dependence between DFT and empirical formation constants, which opens the door for a systematic rescaling.

The self-assembly mechanisms of polyoxometalates (POMs) are still a matter of discussion owing to the difficult task of identifying all the chemical species and reactions involved. The POMSimulator deals with that complexity in an automated manner.     

Tumor microenvironment-oriented adaptive nanodrugs based on peptide self-assembly

The aberrant metabolism of tumor cells creates an inimitable microenvironment featuring acidic pH, high glutathione (GSH) levels, and overexpression of certain enzymes, which benefits the overwhelming progress of a tumor. Peptide self-assembly, emerging as a biofriendly and versatile fabrication strategy, harnesses multiple noncovalent interactions to obtain a variety of nanostructures tailored on demand. Orchestrating the reversible nature of noncovalent interactions and abnormal physiological parameters in the tumor microenvironment enables peptide-based nanodrugs to be targetable or switchable, thereby improving the drugs’ bioavailability and optimizing the treatment outcome. This review will focus on peptide-modulated self-assembly of photosensitizers, chemotherapeutic drugs, immunoactive agents for tumor microenvironment-oriented adaptive phototherapy, chemotherapy, immunotherapy and combinatorial therapy. We will emphasize the building block design, the intermolecular interaction principle, adaptive structural transformation in the tumor microenvironment and corresponding therapeutic efficacy, and aim to elucidate the critical role of peptide-modulated, tumor microenvironment-oriented adaptive assemblies in improving the therapeutic index. Challenges and opportunities will be covered as well to advance the development and clinical application of tumor therapies based on peptide self-assembly materials and techniques.

The tumor microenvironment is of significance to promote release or reorganization of peptide-modulated nanodrugs, optimizing drug bioavailability and therapeutic outcome.     

Designing a highly stable coordination-driven metallacycle for imaging-guided photodynamic cancer theranostics

Coordination-driven self-assembly features good predictability and directionality in the construction of discrete metallacycles and metallacages with well-defined sizes and shapes, but their medicinal application has been limited by their low stability and solubility. Herein, we have designed and synthesized a highly stable coordination-driven metallacycle with desired functionality derived from a perylene-diimide ligand via a spontaneous deprotonation self-assembly process. Brilliant chemical stability and singlet oxygen production ability of this emissive octanuclear organopalladium macrocycle make it a good candidate toward biological studies. After cellular uptake by endocytosis, the metallacycle exhibits potent fluorescence cell imaging properties and cancer photodynamic therapeutic ability through enhancing ROS production, with high biocompatibility and safety. This study not only provides a rational design strategy for highly stable luminescent organopalladium metallacycles, but also sheds light on their application in imaging-guided photodynamic cancer therapy.

A highly-luminescent metallacycle with chemical stability and singlet oxygen production ability were obtained by a spontaneous deprotonation self-assembly process, which exhibits application potential in imaging-guided photodynamic cancer therapy.     

Redesigning donor–acceptor Stenhouse adduct photoswitches through a joint experimental and computational study

Many studies have recently explored a new class of reversible photoswitching compounds named Donor–Acceptor Stenhouse Adducts (DASAs). Upon light irradiation, these systems evolve from a coloured open-chain to a colourless closed-ring form, while the thermal back-reaction occurs at room temperature. In order to fulfill the requirements for different applications, new molecules with specific properties need to be designed. For instance, shifting the activation wavelength towards the red part of the visible spectrum is of relevance to biological applications. By using accurate computational calculations, we have designed new DASAs and predicted some of their photophysical properties. Starting from well-studied donor and acceptor parts, we have shown that small chemical modifications can lead to substantial changes in both photophysical and photoswitching properties of the resulting DASAs. Furthermore, we have also analysed how these substitutions impact the electronic structure of the systems. Finally, some pertinent candidates have been successfully synthesized and their photoswitching properties have been characterized experimentally.

New photoswitch Donor–Acceptor Stenhouse Adducts (DASAs) have been synthesized thanks to accurate computational chemistry predictions. They possess good properties, notably red light activation.     

Capturing photochemical and photophysical transformations in iron complexes with ultrafast X-ray spectroscopy and scattering

Light-driven chemical transformations provide a compelling approach to understanding chemical reactivity with the potential to use this understanding to advance solar energy and catalysis applications. Capturing the non-equilibrium trajectories of electronic excited states with precision, particularly for transition metal complexes, would provide a foundation for advancing both of these objectives. Of particular importance for 3d metal compounds is characterizing the population dynamics of charge-transfer (CT) and metal-centered (MC) electronic excited states and understanding how the inner coordination sphere structural dynamics mediate the interaction between these states. Recent advances in ultrafast X-ray laser science has enabled the electronic excited state dynamics in 3d metal complexes to be followed with unprecedented detail. This review will focus on simultaneous X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS) studies of iron coordination and organometallic complexes. These simultaneous XES-XSS studies have provided detailed insight into the mechanism of light-induced spin crossover in iron coordination compounds, the interaction of CT and MC excited states in iron carbene photosensitizers, and the mechanism of Fe–S bond dissociation in cytochrome c.

Ultrafast X-ray scattering and spectroscopy captures photophysical and photochemical transformations of 3d transition metal complexes with atomistic detail.     

Self-healing and shape memory functions exhibited by supramolecular liquid-crystalline networks formed by combination of hydrogen bonding interactions and coordination bonding

We here report a new approach to develop self-healing shape memory supramolecular liquid-crystalline (LC) networks through self-assembly of molecular building blocks via combination of hydrogen bonding and coordination bonding. We have designed and synthesized supramolecular LC polymers and networks based on the complexation of a forklike mesogenic ligand with Ag⁺ ions and carboxylic acids. Unidirectionally aligned fibers and free-standing films forming layered LC nanostructures have been obtained for the supramolecular LC networks. We have found that hybrid supramolecular LC networks formed through metal–ligand interactions and hydrogen bonding exhibit both self-healing properties and shape memory functions, while hydrogen-bonded LC networks only show self-healing properties. The combination of hydrogen bonds and metal–ligand interactions allows the tuning of intermolecular interactions and self-assembled structures, leading to the formation of the dynamic supramolecular LC materials. The new material design presented here has potential for the development of smart LC materials and functional LC membranes with tunable responsiveness.

New supramolecular hybrid liquid-crystalline networks exhibiting self-healing and shape memory properties are developed by self-assembly of small components through hydrogen bonding interactions and coordination bonding.     

Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 Mpro by QM/MM computational methods

SARS-CoV-2 M^pro is one of the enzymes essential for the replication process of the virus responsible for the COVID-19 pandemic. This work is focused on exploring its proteolysis reaction by means of QM/MM methods. The resulting free energy landscape of the process provides valuable information on the species appearing along the reaction path and suggests that the mechanism of action of this enzyme, taking place in four steps, slightly differs from that of other cysteine proteases. Our predictions, which are in agreement with some recently published experimental data, can be used to guide the design of COVID-19 antiviral compounds with clinical potential.

The molecular mechanism of the proteolysis reaction catalyzed by SARS-CoV-2 M^pro, one of the enzymes essential for the replication process of the virus responsible for the COVID-19 pandemic, is described using computational QM/MM methods.     

Photoswitchable architecture transformation of a DNA-hybrid assembly at the microscopic and macroscopic scale

Molecular recognition-driven self-assembly employing single-stranded DNA (ssDNA) as a template is a promising approach to access complex architectures from simple building blocks. Oligonucleotide-based nanotechnology and soft-materials benefit from the high information storage density, self-correction, and memory function of DNA. Here we control these beneficial properties with light in a photoresponsive biohybrid hydrogel, adding an extra level of function to the system. An ssDNA template was combined with a complementary photo-responsive unit to reversibly switch between various functional states of the supramolecular assembly using a combination of light and heat. We studied the structural response of the hydrogel at both the microscopic and macroscopic scale using a combination of UV-vis absorption and CD spectroscopy, as well as fluorescence, transmission electron, and atomic force microscopy. The hydrogels grown from these supramolecular self-assembly systems show remarkable shape-memory properties and imprinting shape-behavior while the macroscopic shape of the materials obtained can be further manipulated by irradiation.

Molecular recognition-driven self-assembly employing single-stranded DNA (ssDNA) as a template is a promising approach to access complex architectures from simple building blocks.     

Stealth nanorods via the aqueous living crystallisation-driven self-assembly of poly(2-oxazoline)s

The morphology of nanomaterials critically influences their biological interactions. However, there is currently a lack of robust methods for preparing non-spherical particles from biocompatible materials. Here, we combine ‘living’ crystallisation-driven self-assembly (CDSA), a seeded growth method that enables the preparation of rod-like polymer nanoparticles, with poly(2-oxazoline)s (POx), a polymer class that exhibits ‘stealth’ behaviour and excellent biocompatibility. For the first time, the ‘living’ CDSA process was carried out in pure water, resulting in POx nanorods with lengths ranging from ∼60 to 635 nm. In vitro and in vivo study revealed low immune cell association and encouraging blood circulation times, but little difference in the behaviour of POx nanorods of different length. The stealth behaviour observed highlights the promising potential of POx nanorods as a next generation stealth drug delivery platform.

Triggered by heating, a poly(2-alkyl-2-oxazoline) block copolymer undergoes seeded growth in water forming length tuneable nanorods. Morphology and composition combine to impart low immune cell association and promising blood circulation lifetimes.     

Tubularenes

We report the synthesis and characterization of conjugated, conformationally rigid, and electroactive carbon-based nanotubes that we term tubularenes. These structures are constructed from a resorcin[n_b]arene base. Cyclization of the conjugated aromatic nanotube is achieved in one-pot eight-fold C–C bond formation via Suzuki–Miyaura cross-coupling. DFT calculations indicate a buildup of strain energy in excess of 90 kcal mol⁻¹. The resulting architectures contain large internal void spaces >260 ų, are fluorescent, and able to accept up to 4 electrons. This represents the first scaffolding approach that provides conjugated nanotube architectures.

First scaffolding approach to obtain tubular-shaped contorted aromatic architectures.     

Conformational control of Pd2L4 assemblies with unsymmetrical ligands

With increasing interest in the potential utility of metallo-supramolecular architectures for applications as diverse as catalysis and drug delivery, the ability to develop more complex assemblies is keenly sought after. Despite this, symmetrical ligands have been utilised almost exclusively to simplify the self-assembly process as without a significant driving foa mixture of isomeric products will be obtained. Although a small number of unsymmetrical ligands have been shown to serendipitously form well-defined metallo-supramolecular assemblies, a more systematic study could provide generally applicable information to assist in the design of lower symmetry architectures. Pd₂L₄ cages are a popular class of metallo-supramolecular assembly; research seeking to introduce added complexity into their structure to further their functionality has resulted in a handful of examples of heteroleptic structures, whilst the use of unsymmetrical ligands remains underexplored. Herein we show that it is possible to design unsymmetrical ligands in which either steric or geometric constraints, or both, can be incorporated into ligand frameworks to ensure exclusive formation of single isomers of three-dimensional Pd₂L₄ metallo-supramolecular assemblies with high fidelity. In this manner it is possible to access Pd₂L₄ cage architectures of reduced symmetry, a concept that could allow for the controlled spatial segregation of different functionalities within these systems. The introduction of steric directing groups was also seen to have a profound effect on the cage structures, suggesting that simple ligand modifications could be used to engineer structural properties.

Steric and geometric constraints were used to design unsymmetrical ditopic ligands that form single Pd₂L₄ cage isomers with high fidelity.     

Deciphering the evolution of supramolecular nanofibers in solution and solid-state: a combined microscopic and spectroscopic approach

Supramolecular self-assembly of small organic molecules has emerged as a powerful tool to construct well-defined micro- and nanoarchitecture through fine-tuning a range of intermolecular interactions. The size, shape, and optical properties of these nanostructures largely depend on the specific assembly of the molecular building units, temperature and polarity of the medium, and external stimuli. The engineering of supramolecular self-assembled nanostructures with morphology-dependent tunable emission is in high demand due to the promising scope in nanodevices and molecular machines. However, probing the evolution of molecular aggregates from the solution and directing the self-assembly process in a pre-defined fashion are challenging. In the present study, we have deciphered the sequential evolution of supramolecular nanofibers from solution to spherical and oblong-shaped nanoparticles through the variation of solvent polarity, tuning the hydrophobic–hydrophilic interactions. An intriguing case of molecular self-assembly has been elucidated employing a newly designed π-conjugated thiophene derivative (TPAn) through a combination of steady-state absorption, emission measurements, fluorescence correlation spectroscopy (FCS), and electron microscopy. The FCS analysis and microscopy results revealed that the small-sized nanofibers in the dispersion further agglomerated upon solvent evaporation, resulting in a network of nanofibers. Stimuli-responsive reversible interconversion between a network of nanofibers and spherical nanoaggregates was probed both in dispersion and solvent-evaporated state. The evolution of organic nanofibers and a subtle control over the self-assembly process demonstrated in the current investigation provide a general paradigm to correlate the size, shape, and emission properties of fluorescent molecular aggregates in complex heterogeneous media, including a human cell.

Supramolecular nanofiber evolution in solution and solid-state, including stimuli-responsive reversible interconversion among diverse nanoarchitectures, was probed through a combined spectroscopic and microscopic approach.     

The noncovalent dimerization of a G-quadruplex/hemin DNAzyme improves its biocatalytic properties

While many protein enzymes exert their functions through multimerization, which improves both selectivity and activity, this has not yet been demonstrated for other naturally occurring catalysts. Here, we report a multimerization effect applied to catalytic DNAs (or DNAzymes) and demonstrate that the enzymatic efficiency of G-quadruplexes (GQs) in interaction with the hemin cofactor is remarkably enhanced by homodimerization. The resulting non-covalent dimeric GQ–DNAzyme system provides hemin with a structurally defined active site in which both the cofactor (hemin) and the oxidant (H₂O₂) are activated. This new biocatalytic system efficiently performs peroxidase- and peroxygenase-type biotransformations of a broad range of substrates, thus providing new perspectives for biotechnological application of GQs.

Cofactor hemin is sandwiched between 3′ homodimeric G-quadruplexes, leading to an excellent DNAzyme as a mimic of peroxidase and monooxygenase.     

Dissipative self-assembly,competition and inhibition in a self-reproducing protocell model

The bottom-up synthesis of artificial, life-like systems promises to enable the study of emergent properties distinctive to life. Here, we report protocell systems generated from phase-separated building blocks. Vesicle protocells self-reproduce through a phase-transfer mechanism, catalysing their own formation. Dissipative self-assembly by the protocells is achieved when a hydrolysis step to destroy the surfactant is introduced. Competition between micelle and vesicle based replicators for a common feedstock shows that environmental conditions can control what species predominates: under basic conditions vesicles predominate, but in a neutral medium micelles are selected for via a mechanism which inhibits vesicle formation. Finally, the protocells enable orthogonal reactivity by catalysing in situ formation of an amphiphilic organocatalyst, which after incorporation into the vesicle bilayer enantioselectively forms a secondary product.

The bottom-up synthesis of a self-reproducing protocell model enables the study of emergent properties distinctive to life.     

Synthesis of poly(disulfide)s with narrow molecular weight distributions via lactone ring-opening polymerization

We report the first example of controlled polymerization of poly(disulfide)s with narrow molecular weight distributions. 1,4,5-oxadithiepan-2-one (OTP), a disulfide-containing 7-membered ring lactone, was polymerized by using the diphenylphosphate (DPP) catalyzed lactone ring-opening polymerization method. The polymerization proceeded in a living manner, and the resulting polymers displayed very narrow polydispersity index (PDI) values below 1.1 and excellent backbone degradability responding to reducing conditions and UV irradiation.

We report the first example of controlled polymerization of poly(disulfide)s with narrow molecular weight distributions.     

DNA-based constitutional dynamic networks as functional modules for logic gates and computing circuit operations

A nucleic acid-based constitutional dynamic network (CDN) is introduced as a single computational module that, in the presence of different sets of inputs, operates a variety of logic gates including a half adder, 2 : 1 multiplexer and 1 : 2 demultiplexer, a ternary multiplication matrix and a cascaded logic circuit. The CDN-based computational module leads to four logically equivalent outputs for each of the logic operations. Beyond the significance of the four logically equivalent outputs in establishing reliable and robust readout signals of the computational module, each of the outputs may be fanned out, in the presence of different inputs, to a set of different logic circuits. In addition, the ability to intercommunicate constitutional dynamic networks (CDNs) and to construct DNA-based CDNs of higher complexity provides versatile means to design computing circuits of enhanced complexity.

A nucleic acid-based constitutional dynamic network (CDN) provides a single functional computational module for diverse input-guided logic operations and computing circuits.