Chiral supramolecular nanomaterials: From chirality transfer and amplification to regulation and applications

Chirality is an omnipresent structural feature found in nature. The transfer and amplification of chirality are widely recognized phenomena. In appropriate solvents, chiral molecules can self‐assemble into diverse chiral supramolecular nanomaterials with unique properties. In the past two decades, there has been a growing number of reported chiral supramolecular nanomaterials. Significant advancements have been made in the transfer and amplification of chirality within these materials, as well as their regulation and applications. Therefore, it is essential to summarize the progress made in this field. Here we present a comprehensive overview of the latest advancements in chiral supramolecular nanomaterials, ranging from chirality transfer and amplification to regulation and applications. This review aims to deepen our understanding of the fundamental origins of inherent chirality in the chiral supramolecular nanomaterials, while also providing a reference for expanding their potential applications.


| INTRODUCTION
Chirality is a widely observed phenomenon in nature at the molecular level, as evidenced by the presence of D-sugars and L-amino acids.Furthermore, the concept of chirality is ubiquitous and can be discerned across multiple levels of hierarchy [1] (Figure 1).Chirality at the subatomic level is linked to the parity conservation law.
At the molecular level, the natural system comprises a significant quantity of chiral molecules, including amino acids and carbohydrates, while numerous artificially produced chemicals exhibit high chirality.In addition, a plethora of biological macromolecules and supramolecular systems demonstrate chirality, including the tobacco mosaic virus, alongside macroscopic living organisms, like, snails.At a larger scope, numerous plant species, including Virginia creeper, exhibit chiral symmetry.The galaxy system exhibits chirality on a light-year scale.

| CHIRALITY TRANSFER AND AMPLIFICATION IN SUPRAMOLECULAR SYSTEMS
The phenomenon of chirality transfer and amplification is widely acknowledged in conventional covalent polymers.Lifson et al. have conducted groundbreaking research on the poly-(alkyl isocyanates) system. [16]Two distinct phenomena were identified that exert influence on the enhancement of chirality, commonly known as the "sergeants-and-soldiers" principle and the "majorityrules" effects. [17][20] Figure 2 illustrates the underlying principles involved in the augmentation of chirality within self-assembled systems.
F I G U R E 1 Chiral architecture exists on a broad variety of scales, including neutrinos, enantiomeric molecules, nanoscale biomolecules with chiral structures, macroscopic biological systems, and galaxies.The protein structure image was collected from Wikipedia and used under the terms of Wikipedia's license for "fair use."Live plant leaves image is reprinted with permission from http://www.speciesorchids.com/CeretobeDendrobiums.html.The galaxy picture is a free stock graphic obtained from https://www.rgbstock.com/bigphoto/mVErmjU%2FSpiral+Galaxy.
F I G U R E 2 Schematic illustration of chirality at various levels, including molecular, supramolecular, and aggregation levels.
The primary challenge in the context of the rule governing sergeant-and-soldier systems is to determine the minimum number of sergeant molecules required to maintain control over supramolecular chirality.Initially, a significant number of symmetrical entities (soldiers) follow instructions from a limited set of asymmetrical entities (sergeants).The principle of majority rules applies when a minor excess of one enantiomer results in a substantial bias towards the same helical direction throughout the aggregate.

| CHARACTERIZATION OF CHIRAL SUPRAMOLECULAR NANOMATERIALS
Chiral supramolecules possess the ability to undergo selfassembly in a suitable solvent, leading to the emergence of nano or microscale superstructures, such as fibers, ribbons, sheets, and spheres.This process ultimately leads to the formation of three-dimensional (3D) networks.The diverse nature of supramolecules, which imparts them with distinctive characteristics, renders their characterization multifaceted.Multiple techniques are available for the characterization of supramolecules, such as nuclear magnetic resonance (NMR) spectroscopy, X-ray techniques, spectroscopy, microscopy techniques, and computational techniques. [21,22]he investigation of supramolecules through NMR spectroscopy is based on its distinctive capability to examine the surroundings of a single atomic nucleus, thereby providing information on the structures and movements of the networks that are formed.NMR spectroscopy has the capacity to furnish insights into the structural characteristics of the constituents, the resulting assemblies, and the domains involved in the intermolecular associations, all of which are crucial factors in the resilience of the kinetic networks.Conversely, the NMR method is powerful in the analysis of supramolecules because of the relatively prolonged relaxation periods of the detected nuclei.Yu et al. demonstrated the construction of a multiresponsive supramolecular polymer network gel through orthogonal self-assembly, showcasing its temperature-dependent gel-sol transition convincingly using 1 H NMR spectra. [23]mall-angle X-ray scattering (SAXS) is utilized as an X-ray method to explore supramolecular assemblies' structures in the nanometer to micrometer range.To achieve this, the scattering intensity is measured at scattering angles (2θ) near 0°.The characterization of supramolecular materials, typically composed of fiberlike structures interconnected by multiple noncovalent interactions, is significantly enhanced through the utilization of SAXS.This methodology facilitates the assessment of the dimensions, morphology, and dispersion of these fibers.Huang et al. reported the gelators with L-lysine-based dendritic headgroups. [24]The SAXS data provided compelling evidence for the formation of a sausage-like morphology exhibiting nanoscale features.
CD is a highly valuable technique for conveniently examining the stereo structures, as well as intra-and intermolecular interactions, of diverse types of chirality.The analysis of the structural properties of chiral supramolecular systems can be effectively performed using CD spectroscopy.This technique offers enhanced sensitivity to molecular conformation and configuration, surpassing that of achiral absorption spectroscopy methods, like, ultraviolet, visible (Vis), and infrared (IR) spectra.CD spectroscopy is widely used in various fields, including the examination of the structure of small organic compounds, DNA, and proteins, owing to its numerous benefits.Rodríguez et al. reported a supramolecular gel containing a Pro-Val moiety, in which intramolecular folding occurred in the sol state as confirmed by CD spectroscopy, exhibiting two negative bands and a positive lobe typical of a helix. [25]he atomic force microscopy (AFM), a well-known tool, is used to image, measure, and manipulate materials at the nanoscale.The utilization of AFM presents numerous benefits in the examination of supramolecular structures on surfaces.The AFM, a flexible instrument, can be utilized for observing detailed images at various length scales, spanning from nanometers to submillimeters.Furthermore, the AFM has the ability to offer a surface profile in three dimensions.Its applicability extends to both gaseous and liquid environments.In addition, the AFM does not require any specific handling of samples, such as applying metal or carbon coating, which might lead to permanent alterations or harm to the samples.Furthermore, the AFM usually generates final images that are not affected by charging artifacts.Rao et al. reported a supramolecular hydrogel, wherein AFM was employed to gain deeper insights into the selfassembly of the charge-transfer complex into 1D nanofibers and the subsequent formation of a hydrogel. [26]t is possible to use computational techniques to simulate the behavior of molecules and atoms.The foundation of this framework is established on the fundamental elucidations of atomic and molecular orbitals, commonly known as ab initio quantum mechanics.Moreover, prior knowledge of molecular mechanics allows for the utilization of experimental data.Alternatively, semiempirical methods can be employed by utilizing a combination of both approaches.In the majority of instances, obtaining single crystal structures is unfeasible for providing direct insight into interactions within the solid state.Computational techniques are crucial in exploring the intermolecular interactions of supramolecules, thereby facilitating comprehension of the underlying self-assembly mechanisms.Velichko et al. employed a coarse-grained model approach to investigate the selfassembly of a peptide amphiphile molecule, which is driven by hydrogen bonding interactions between peptide blocks. [27]

| MODULATION OF CHIRALITY IN SUPRAMOLECULAR SELF-ASSEMBLY PROCESSES
The chirality of supramolecular assemblies is well suited for a diverse array of supplementary stimuli (Figure 3), owing to their exceptional adaptability.0]

| Solvent
The presence of a solvent is crucial in the assembly process, as it can significantly influence the spatial arrangement of resulting nanostructures through its interaction with the solute.Various essential properties of solvents, including but not limited to their polarity, viscosity, and solubility for the solute and other substances, can affect the supramolecular chirality of a supramolecular system. [37]u et al. developed two categories of chiral gelators using L-glutamide as a base, featuring headgroups of pyridine-modified cyanodiarylethene (L/D-PyPhG and L-PyG). [31]Both amphiphiles were discovered to create gels in dimethyl sulfoxide and assemble themselves into clockwise nanotwists.Conversely, in ethanol, they F I G U R E 3 Regulation of chirality via a variety of extrinsic stimuli.(A) The self-assembly of L-PyPhG and L-PyG molecular structures is influenced by the solvent.The two gelators assembled into left-handed nanotubes in ethanol, while they could gelate DMSO to form right-handed nanotwists.Reproduced with permission. [31]Copyright 2022, with permission from the American Chemical Society.(B) Demonstration of the thermosensitive and adjustable chirality of dendronized TPEs through self-assembly is depicted.Reproduced with permission. [32]Copyright 2021, with permission from the American Chemical Society.(C) Morphology evolution and self-assembly behavior under the influence of ultrasonication.Reproduced with permission. [33]Copyright 2023, with permission from Wiley-VCH.(D) SAv-mediated cross-linking and surface binding of supramolecular polymers.Reproduced with permission. [34]Copyright 2022, with permission from Wiley-VCH.(E) pH-controlled chirality inversion in enantiodifferentiating photocyclodimerization.Reproduced with permission. [35]Copyright 2020, with permission from the American Chemical Society.(F) Depiction of the suggested mechanism for the chiral organization of Azo polymers induced by CPL.Reproduced with permission. [36]Copyright 2022, with permission from Wiley-VCH.AC, 2-anthracenecarboxylic acid; BTAM, benzene-1,3,5-tricarboxamide motif with an aminopyridine group; CD, circular dichroism; CPL, circularly polarized luminescence; DMSO, dimethyl sulfoxide; ET, Förster resonance energy transfer; SAv, streptavidin; TPEs, tetraphenylethylenes.
formed suspensions composed of counterclockwise nanotubes (Figure 3A).The revelation indicated that the varied actions caused by the two solvents were intricately connected to the subtle noncovalent interactions and consequently distinct packing methods of the gelators.The research conducted by them presented a remarkable example of self-assembly that is regulated by protic/aprotic solvents.This study emphasizes a straightforward methodology capable of modulating the efficiency of energy transfer without altering the characteristics of the donor and acceptor.
Qin et al. prepared a pair of L-tryptophan methyl ester appendages linked to the paradisubstituted phenyl (LPWM). [38]In ethanol, LPWM was observed to spontaneously form nanospheres, while in H 2 O it formed right-handed nanofibers.Through precise control of the proportion of ethanol to H 2 O in the blended solutions, an intriguing metamorphosis from nanospheres to superhelices was witnessed.The results broaden comprehension of self-organization in dimensional and morphological change, and offer a new method for producing sophisticated functional substances that imitate biological structures.
In a CHCl 3 /THF solution, Zhang et al. reported a temporary assembly mechanism where the development of structure and luminescence of assemblies is controlled by small amounts of water. [39]By manipulating the moisture content and implementing alternative assembly configurations, the system can exhibit various evolutionary pathways, control the lifespan of supramolecular polymers, and modify the temporal luminescent properties of the system.

| Temperature
As previously stated, the process of self-assembly is heavily dependent on hydrogen bonding, which exhibits decreased strength with increasing temperature.Consequently, alterations in temperature exert an intense influence on chiral assemblies that depend on hydrogen bonding.The attribute of thermal reversibility plays a crucial role in the self-assembly process of chiral supramolecular hydrogels.The impact of temperature on the strength of noncovalent interactions is a significant factor to consider.The method commonly employed for the production of supramolecular gels involves dissolving molecules in water and subsequently inducing gel formation through the process of cooling.The phenomenon of thermoregulation in chiral assemblies is frequently observed in supramolecular gels that rely on hydrogen bonding. [40,41]iu et al. suggested the utilization of tetraphenylethylene (TPE) as the nonpolar center for constructing the supramolecular monomer by dendronization with hydrophilic threefold dendritic oligoethylene glycols through a dipeptide connection to generate a category of amphiphilic dendronized TPEs. [32]The thermoresponsive behavior of these small spherical clusters was observed (Figure 3B).Chiral spheres that respond to temperature play a crucial role in imitating biological processes and hold great potential in the field of smart materials.

| Sonication
Ultrasound is commonly utilized as an energy stimulus to disrupt and consolidate hydrogen bonding, π-π stacking, and hydrophobic interactions between molecular entities, while also altering the organization and configuration of the assembled constituents.
Sang et al. conducted an extensive investigation on the process of supramolecular gelation induced by ultrasound, which was accompanied by a phenomenon of mirror symmetry breaking. [33]AgI was coordinated with a benzene-1,3,5-tricarboxamide motif with an aminopyridine group containing aminopyridine groups in each arm, resulting in the self-assembly of nanospheres.Upon the application of sonication, a disruption in symmetry took place, leading to the transformation of the nanospheres into helical nanofibers that exhibited robust CD signals (Figure 3C).
During the process of aggregation in solution, Liu et al. revealed the finding of a group of achiral polymers connected by imine linkages, possessing both crosslinked and linear topological structures. [42]These polymers exhibited the ability to spontaneously form helical nanofibers under the influence of sonication.The research offered a novel approach to create spiral nanomaterials using nonchiral components.

| Interface
In recent years, there have been reports on the emergence of novel chiral discrimination systems utilized in electrochemical detection and biochemical sensing.These systems have been identified as chiral interface materials.45][46] Xiu et al. introduced a completely noncovalent network system comprised of synthetic supramolecular polymers that engage with one another and other entities in a deliberate and precise manner. [34]The supramolecular polymer is created in an aqueous medium, utilizing the coassembly of biotinylated building blocks that are structurally similar and chiral aromatic building blocks.This water-based environment is conducive to existing platforms for natural and biomimetic systems, resembling real-life conditions.The inclusion of biotin components in supramolecular polymer systems allows for the polymer cross-linking when streptavidin (SAv) is added, and also facilitates the connection of these polymers to surfaces that mimic cell membranes modified with SAv (Figure 3D).

| pH value
The pH value of the solvent can be manipulated to achieve modulation of hydrogen bonds.The reversal of helicity is frequently caused by alterations in pH, which induce changes in peptide conformation and interactions among amino acid-based building blocks. [47,48]anagaraj et al. presented γ-cyclodextrin (γ-CDx) analogs as chiral hosts for the photocyclodimerization of 2-anthracenecarboxylic acid (AC). [35]The investigation focused on the impact of pH on the photoreactivity and the resulting stereochemistry of the photoproducts.The stereochemical outcome of head-to-head conformer cyclodimer 3 was reversed from 25.2% to −64.4% and 41.2% to −76.2%, respectively, when the pH of the solution was altered (Figure 3E).The results they discovered provide a new opportunity for managing the supramolecular chirality using chiral hosts found in nature.
The coassembly behavior of Phe-Phe dipeptides with 1,2-diaminoethane at various pH levels was examined by Jiang et al. [49] By conducting their investigation, they enhance our comprehension regarding the source of the circularly polarized luminescence (CPL) signals and present a novel method to manipulate the chirality of CPL through the combination of coassembling and pH regulation.

| Light
The utilization of Vis light can drive dynamic covalent imine assemblies out of equilibrium.When compared with chemical fuels, the utilization of light for remote control presents a cost-efficient alternative that exhibits superior temporal and spatial resolution, while concurrently minimizing waste generation.52][53][54][55][56][57] Xu et al. investigated the emission of T-CPL and CPL with elevated g values from chiral CNC films to induce the helical arrangement of supramolecular polymers. [36]igure 3F illustrates the transformation of amorphous Azo polymers with varying spatial lengths from a state of disorder to chiral structures through T-CPL induction.The research they conducted offered new perspective on the asymmetric photochemistry initiated by CPL in materials derived from biological sources and inspired by biology.This breakthrough could potentially pave the way for achieving light-controlled chirality on a mesoscopic level.
Sun et al. reported a photoactivated system that allows precise manipulation of the arrangement of nanoparticles (NPs) into nanofibers within living cells by utilizing subtle alterations in molecular conformation and internal hydrogen bonding interactions. [58]The results indicate that the use of light-induced controllable assembly can be employed to actively regulate cellular behaviors in living organisms.Nieland et al. demonstrated the creation of various dissipative or metastable dynamic covalent systems by utilizing photons as a trigger, enabling manipulation of the quantity of monomers engaged in cyclo-oligomerization, resulting in both ring contraction and expansion. [59]

| Other factors
The phenomenon of supramolecular assembly, which involves the construction of hierarchical structures through metal coordination, is widely recognized as a highly efficient method that is facilitated by the presence of metal ions.During the self-assembly process, Min et al. examined the coordination assembly of the ferrocenediphenyalanine (Fc-LFLF) with various transition-metal ions by introducing different metal ions. [60]The phenomenon of chirality inversion has been successfully demonstrated in specific transition-metal complexes by inducing changes in coordination/valence preferences across different oxidation states through redox processes. [61,62]Xiao et al. developed the chiral electrochemically sensitive molecular universal joint (EMUJ) through the integration of a macrocyclic pillar [6]arene with a side ring derived from ferrocene. [63]The selfinclusion/exclusion conformational switch of the EMUJ molecule, induced by redox reactions of the ferrocene group it is bound to, is closely linked to the occupancy or the absence of the P [6] cavity.Consequently, an extraordinary electrochemically controlled interaction and subsequent liberation of the guest were observed.

| Optical
Considerable investigation has been undertaken regarding notable attributes such as chiral amplification, chiral induction, and chiral memory within supramolecular aggregates.[66] The MRE indicates that a small surplus of one enantiomer leads to a significant inclination towards the preferred helical direction of the major enantiomer.In such instances, the optical rotation, typically detected through CD spectra, of the helical assemblies formed from enantiomeric mixtures with different enantiomeric excess (ee) is greater than what would be anticipated based on a linear correlation.69] Chiroptical switches can be generated through the incorporation of chiral information into molecular or supramolecular switchable systems.Chiroptical signals are typically represented by optical rotatory dispersion (ORD), CD, and CPL.As a result, the chiroptical switch system has the ability to switch between two states, exhibiting distinct ORD, CD, or CPL signals.72] The integration of chiral aggregated superstructures was used by Chen et al. to describe a new aggregationinduced emission (AIE) phenomenon. [73]The occurrence of chiral aggregation leads to the formation of nanofibers and microloops on the surface of mica.In addition, the clusters that are shaped like rings exhibit characteristic AIE properties that can be attributed to different intermolecular interactions (Figure 4A).Li et al. created a unique organic supramolecular zipper system consisting of a single element, which had a lifespan of 0.77 s. [74] The extensive experimental and theoretical analyses demonstrated the assurance of long-distance π-stackings in the self-assembling supramolecular zippers (Figure 4B).The discovery provides a fresh set of principles for the development of ultralong organic phosphorescence (UOP) molecules consisting of a single component and offers a novel viewpoint on the UOP mechanism.
Ma et al. created a variety of new fluorophores by combining bridged phenyl pyridinium salts with donor-acceptor groups connected through flexible alkyl chains.After being included in a rigid matrix, [75] the supramolecular pin 1/CB [8] exhibits afterglow with an exceptionally high phosphorescence quantum yield (99.38%), surpassing the previously reported yields for phosphorescent materials (Figure 4C).The research they conducted has the potential to be useful in advancing the creation of completely organic phosphors for purposes such as biological imaging and preventing counterfeiting.Jiang et al. employed the adaptable photonic bandgap of a self-assembled supramolecular material known as ferroelectric liquid crystal-doped cholesteric liquid crystal (FLC-CLC), which was doped with FLC. [76]Additionally, they utilized the electrothermal property of the transparent indium tin oxide film.The application of this innovative approach led to the creation of a low-voltage adjustable photonic device that has the ability to produce output that closely resembles a full-color representation.The manufactured polymer/FLC-CLC coaxial microfibers and fabric possess the capability to undergo electrical adjustment of their color within a specified low-voltage range (1.5-3.5 V) at a temperature of 23°C.This adjustment allows for a transition in color from red to blue, as depicted in Figure 4D.

| Cell adhesion
The adherence to external surfaces has substantial implications for the organization and behavior of cells, particularly those that are dependent on anchorage. [77]ell adhesion to the substrate is often perceived as a multifaceted and varied process at the molecular level, involving cell attachment and spreading, formation of focal adhesions, deposition of extracellular matrix, and rearrangement. [78]Significant findings have been revealed in the realm of bioactivity, specifically regarding cell adhesion and spreading, as well as the potential for materials to be altered to promote cell adhesion. [79,80]eung et al. have reported a technique that relies on supramolecular interactions to generate reversible selfassembled monolayers characterized by tunable lateral mobility and the capacity to dynamically manipulate surface composition, thereby governing cell adhesion behavior. [81]The sensing mechanism employed by this system entails the utilization of noncovalent ion pairs between amidinium and carboxylate to facilitate the creation (on) and dissolution (off) of stable 2D structures.These structures bear a resemblance to lipid bilayers but can be easily prepared and exhibit rapid on/off rates, as depicted in Figure 5A.They have showcased a flexible instrument for examining and managing cellular attachment and specialization, presenting intriguing possibilities for cell and tissue engineering.In their study, Wang et al. presented a technique called microservice architecture for creating 3D organized patterns containing varied chemical components inside, aiming to achieve specific cell adhesion. [82]The 3D arrangement is created by aligning polydimethylsiloxane (PDMS) components using the magnetic pick-and-place technique, followed by interfacial connections between PDMS based on host/ guest molecular recognition (Figure 5B).The approach they employ can introduce a customizable construction idea to produce an intricate 3D framework with a wide range of chemical and biological variations, including the precise 3D arrangement of particular biomolecules and diverse cell types.Diba et al. utilized B-and M-type compounds containing ureido-pyrimidinone units as fundamental components in the construction of supramolecular architectures. [83]The research findings demonstrate the importance of molecular exchange dynamics in the effective functionalization of supramolecular hydrogels (Figure 5C).
In their study, Cringoli et al. discovered that D-Phe- Phe-Leu, an unshielded tripeptide, has the capability to spontaneously form twisted fibers with a right-handed structure. [84]These fibers can then form stable hydrogels under physiological conditions.Hydrogels created from peptides stimulated β1 integrin proteins, resulting in cell attachment and expansion, and demonstrated excellent cell survival.The inclusion of uncapped, short D,L-peptide biomaterials in their work expands the variety of applications available.
The optical applications of chiral supramolecular nanomaterials.(A) The assembly of the D,D-G1 modified C 3 -symmetric molecule resulted in the creation of luminescent microloops, whereas L,L-G1 aggregates exhibited the presence of nanofibers.Reproduced with permission. [73]Copyright 2017, with permission from Royal Society of Chemistry.(B) The secondary prevention of art counterfeiting can be accomplished through the utilization of the suggested mechanism of ultralong organic phosphorescence and the application of SF2Pz.Reproduced with permission. [74]Copyright 2022, with permission from Wiley-VCH.(C) Creation of supramolecular pin 1/CB [8], potential mechanism for enhanced and shifted phosphorescence, and images from confocal microscopy.Reproduced with permission. [75]opyright 2021, with permission from Wiley-VCH.(D) Coaxial electrospinning technique was utilized to obtain electrothermochromic microfibers.Reproduced with permission. [76]Copyright 2021, with permission from Wiley-VCH.ICT, intramolecular charge transfer; ISC, intersystem crossing transition; SF2Pz, 4,4'-sulfonylbis(fluorobenzene) motif with two pyrazole groups; SFPz is short for 4,4'-sulfonylbis (fluorobenzene) motif with a pyrazole group; SFPP, 4,4'-sulfonylbis(fluorobenzene) motif with a pyrazole group and a phenothiazine group; UOP, ultralong organic phosphorescence; UV, ultraviolet.
Ishida et al. discovered that A2G created a self-assembly of β-sheet, resulting in nanofibers, whereas A6G predominantly formed nonfibrous structures characterized by αhelix and random coil formations.A2G exhibited less twisted β-sheet compared with A10G and A14G, resulting in the formation of assembled nanofibers.A10G and A14G exhibited superior cell adhesion properties compared with the remaining RGD-containing peptides, indicating that the cell adhesion is influenced by favorable conformations and/ or clustering of the RGD moieties. [85] helical chirality system that can be adjusted was created by Lu et al. using phenylalanine (Phe) based on C 2 -symmetric benzene-paradicarboxamide. [86] The cellular actions suggest that the impacts of supramolecular chirality at a higher level have a greater effect on cell growth and survival compared with the effects of individual chirality.
characterized by means of spectral measurements or the determination of crystal structures, which enable the detection and analysis of diverse interactions involved in this phenomenon.The application of metal-directed self-assembly offers unique opportunities for the creation of well-defined coordination architectures and has led to notable progress in the advancement of functional porous cages. [87]90] Qing et al. found that nonchiral solvents have the ability to modulate the chiral transfer process, leading to a reversal of chiral interaction and facilitating the formation of organogel. [91]The clear distinction in gelation rate and the structure of the resulting self-assembly allows for the observation of this process.The successful application of this chiral phenomenon in separating quinine enantiomers gives the gel materials "smart" advantages (Figure 6A).The research they conducted offered a valuable understanding of the formation of chiral gels and its associated applications, including the separation of enantiomers.Lin et al. described a technique for labeling fluorescence using luminescent metal-phenolic networks made from metal ions, phenolic ligands, and readily accessible dyes that are commonly found in the market. [92]The fluorescent coatings show minimal cytotoxicity and maintain their intense fluorescence even after being taken up by intracellular compartments (Figure 6B).Anticipated is the versatility of their approach to fluorescence labeling, which holds promise in various domains within the physical and life sciences.Wang et al. announced the discovery of a fresh category of macrocyclic hosts called methylenebridged naphthotubes, which possess clearly defined hollow spaces. [93]The naphthotubes with methylene bridges exhibit high affinities for binding and can serve as sensors for detecting the chirality of organic cations (Figure 6C).Their study revealed significant characteristics in molecular identification and chiral perception, further enhancing the repertoire of supramolecular chemistry.
In their study, Hu et al. discovered an unconventional amino acid called 2-nitroimidazol-1-yl alanine and The sensing and recognition applications of chiral supramolecular nanomaterials.(A) Illustration of the ultrasoundpromoted self-assembly processes of G1.Reproduced with permission. [91]Copyright 2014, with permission from Wiley-VCH.(B) Assembly of L-MPNs on various particles.Reproduced with permission. [92]Copyright 2021, with permission from Wiley-VCH.(C) Chemical structures of the chiral guests, and energy-minimized structures of R-15@NT3-Me, S-15@NT3-Me, R-18@P-NT4-Me, and R-18@M-NT4-Me.Reproduced with permission. [93]Copyright 2022, with permission from Wiley-VCH.G1, small-molecular gelator 1; L-MPNs, luminescent metal-phenolic networks; NPN, N-phenyl-1-naphthylamine; RhB, rhodamine B. investigated its role in developing peptide-based supramolecular probes that respond to nitroreductase for effective hypoxia imaging. [94]The results they obtained show the progress in creating a flexible and easily produced amino acid that has demonstrated properties in forming fluorescent peptide nanostructures that can respond to a biological microenvironment.This discovery offers a valuable set of tools for synthetic biology and the advancement of new biomaterials.
Liu et al. showcased a chiroptical platform utilizing plasmonic circular dichroism (PCD) for the analysis of molecular chirality. [95]The asymmetrically amplified PCD readouts are derived from chiral host-guest recognitions by utilizing chiral plasmonic nanotransducers in their design.The discoveries they have made can provide a wide foundation for identifying chiral organic compounds, which could have significant implications in biotechnology, especially in the pharmaceutical sector.

| Imaging
Li et al. devised a supramolecular technique for producing a nanostructured phototheranostic substance by directly assembling two water-soluble variations of phthalocyanine, namely, zinc Pc tetrasubstituted with 4sulfonatophenoxy groups (PcS4) and zinc Pc tetrasubstituted with 3-(N,N,N-trimethylammonium) phenoxy groups (PcN4). [96]According to in vivo assessments, PcS4-PcN4 has the potential to effectively detect a tumor with strong differentiation using whole-body photoacoustic imaging, while also facilitating exceptional photothermal treatment for cancer (Figure 7A).The utilization of a supramolecular ternary assembly with near-IR (NIR) fluorescence emission has been reported by Shen et al., demonstrating its efficacy in imaging A549 cells. [97]The introduction of HA-CD resulted in an increased emission of NIR, which enhanced the assembly The imaging applications of chiral supramolecular nanomaterials.(A) Schematic illustration of the fabrication of a nanostructured contrast agent.Reproduced with permission. [96]Copyright 2020, with permission from Wiley-VCH.(B) Schematic Illustration of the formation of supramolecular nanoparticle with NIR emission.Reproduced with permission. [97]Copyright 2021, with permission from Wiley-VCH.CD, circular dichroism spectroscopy; PA, photoacoustic; TPEs, tetraphenylethylenes.
with TPE-2SP/CB [8] and led to the formation of supramolecular NPs (Figure 7B).The novel supramolecular assembly system effectively addresses the challenges of short wavelength excitation and emission encountered by earlier supramolecular imaging systems.It demonstrates the benefits of minimal phototoxicity, enhanced deep tissue penetration, and superior imaging precision.Furthermore, it introduces innovative possibilities for utilizing supramolecular systems in the field of biology, particularly in cell imaging.
Li et al. created a deep learning framework that uses an innovative machine vision algorithm, a specially designed data selection method, and effective data augmentation techniques. [98]This framework enables the automated recognition of intricate scanning probe microscopy patterns using a single image and system.For the initial time, Duan et al. discovered that porphyrin derivatives exhibit inherent long-lasting luminescence in the NIR area even after the excitation light stops or when they interact with peroxynitrite (ONOO-).In contrast, prior research exclusively employed porphyrin derivatives as photosensitizers (PSs) and fluorescent and/or photothermal agents. [99]The study presents a novel category of optical agents that can transform imaging modalities and have adaptive imaging capabilities, thereby significantly speeding up the process of drug evaluation.

| Catalysis
Weak interactions, specifically hydrogen bonds, are utilized by nature to form supramolecular architectures that possess biological activity.This is evidenced by the observation of 3D structures in enzymes and nucleic acids.There has been a significant interest in the exploration and application of supramolecular catalysts within the fields of selective chemical synthesis and molecular recognition.105] Sun et al. created a 3D chiral setting for lipase by transferring the chiral properties from tiny compounds to polymers lacking chirality. [106]The lipase trapped in the 3D chiral setting demonstrates remarkable catalytic effectiveness, reusability, and recyclability.Additionally, evaluations are conducted to analyze alterations when incorporating enzymes with diverse chiral settings (Figure 8A).The idea of creating a 3D chiral microenvironment has the potential to greatly impact various industries, such as biocatalysis, drug delivery, biosensing, and medical devices, through the The catalysis applications of chiral supramolecular nanomaterials.(A) General procedures for the preparation of a 3D chiral microenvironment for lipase.Reproduced with permission. [106]Copyright 2021, with permission from American Chemical Society.(B) Chirality-dependent coordination assembly process between FF molecules and Cu 2+ .Reproduced with permission. [107]Copyright 2022, with permission from American Chemical Society.(C) A supramolecular coordination bonding-based dynamic vesicle.Reproduced with permission. [108]Copyright 2022, with permission from American Chemical Society.FF, diphenylalanine peptide (Phe-Phe); NADH, reduced nicotinamide adenine dinucleotide; PVA, poly (vinyl alcohol).advancement of enzyme immobilization technologies.Zhang et al. modified the chirality of the peptide to improve its physicochemical characteristics by utilizing the coordination assembly of diphenylalanine peptide and divalent copper ions. [107]In contrast, the (L + D)-FF-Cu demonstrates enhanced calculated catalytic efficiency and reusability in comparison to (L)-FF-Cu due to its heightened stability in aqueous environments (Figure 8B).By manipulating the chirality of constituent units, this study presents an effortless approach to create versatile materials with adjustable structure and characteristics.Solra et al. created a dynamic vesicle using supramolecular coordination bonding, which demonstrates multiple enzymatic functions. [108]The supramolecular nanozyme exhibits efficient laccase-like catalysis, surpassing the native enzyme in terms of Michaelis constant value, and demonstrating enhanced stability even under harsh conditions (Figure 8C).In this study, a novel approach is presented to achieve a synthetic supramolecular system capable of regulating the activity of multiple enzymes in the presence of ecofriendly fuel and waste materials.
Smith et al. developed a supramolecular method for electrochemical oxygen reduction reaction catalysis in water with a neutral pH value. [109]This approach utilizes site isolation and porosity to enhance the preference for the 2e− reduction, resulting in the production of H 2 O 2 with 100% selectivity, surpassing the thermodynamically favored 4e− H 2 O product.Expanding beyond conventional host-guest interactions, the capacity to regulate reaction selectivity in supramolecular structures presents novel prospects in the design of these architectures for a wider array of catalytic applications.
Through a supramolecular recognition process, Walsh et al. demonstrated the ease of achieving control over the chirality of ammonium cations. [110]Excellent yields and selectivity can be achieved by producing chiral ammonium cations through the combination of enantioselective ammonium recognition using 1,1′-bi-2naphthol scaffolds and conditions that induce racemization of the nitrogen stereocenter.
A novel approach was devised by Jiao et al. to construct distinct chiral helicates using axially chiral ligands of the 1,1′-biphenyl type through self-assembly. [111]The helicates can create chiral microenvironments that are limited in space and contain different polar and nonpolar parts.These parts have a significant impact on the binding affinities and chiral discrimination properties of the helicates.

| Drug carrier
In recent years, there has been significant progress in the field of cancer treatment, particularly in the utilization of NP-based drug delivery systems.This is primarily attributed to the enhanced permeability and retention (EPR) effect, which leads to improved pharmacokinetics and biodistribution profiles. [112,113]Nevertheless, the EPR effect solely improves the gathering of NPs in tumor tissues.Nonetheless, the inadequate cellular uptake and inadequate intracellular drug discharge consistently restrict the doses of anticancer medications to a level lower than the therapeutic range, thereby impeding the effectiveness of cancer chemotherapy.116] Liu et al. described a systematic method to regulate the size of individual metal-organic cages and transform them into supramolecular NPs, with the aim of facilitating the delivery of proteins inside cells and determining cell destiny. [117]The researchers showed that the hierarchical self-assembly procedure retains its exceptional effectiveness and independence when protein is present, allowing for the formation of supramolecular NPs containing protein for delivering proteins inside cells and editing genomes (see Figure 9A).Wang et al. created an advanced series of nanodrug carriers using recombinant proteins, which exhibit high efficacy in encapsulating and transporting the hydrophobic aldoxorubicin prodrug. [118]The nanomedication's treatment profiles were much more effective than free aldoxorubicin.These profiles were identified through the presence of subcutaneous solid tumors and bone tumor xenografts in vivo (Figure 9B).
To achieve effective drug delivery, Zhang et al. created a supramolecular assembly of graphene oxide (GO) with peptides, resulting in a significant improvement in drug-loading and drug-releasing capabilities. [119]y utilizing peptide capping and drug loading through supramolecular interactions, the GO supramolecular assembly achieved efficient drug loading and exhibited drug release sensitivity to alternating magnetic field.

| therapy
130][131][132][133][134][135][136][137][138] Chang et al. conducted a study wherein they synthesized peptide-PS compounds and investigated their phototherapeutic characteristics. [139]Different noncovalent interactions led to the formation of nanodrugs with unique morphologies during the selfassembly of the conjugates.Regardless of their amino acid sequences and nanostructures, all of the nano drugs demonstrated significant photothermal conversion efficiencies.The results of the therapeutic outcomes suggest that PTT was the dominant mechanism, and it was found that ensuring the structural stability of nano drugs in biological environments was essential for achieving effective PTT (see Figure 10A).Zhao et al. employed lanthanide NPs loaded with hypericin (Hyp) and coated with MnO x to create UCNP@MnO x -Hyp. [140]This The drug carrier applications of chiral supramolecular nanomaterials.(A) Self-assembly of adamantane-functionalized M 12 L 24 metal-organic cages (MOC) and PEI-βCD.Reproduced with permission. [117]Copyright 2021, with permission from Wiley-VCH.(B) Fabrication of PCP-PEG-ALD assemblies, and investigation of the anticancer effect of the nanodrug on mice.Reproduced with permission. [118]Copyright 2021, with permission from Wiley-VCH.βCD, β-cyclodextrin.ALD, aldoxorubicin; PCP, positively charged proteins; PEG, polyethylene glycol; PEI, polyethylenimine; SNP, supramolecular nanoparticles.

F I G U R E 10
The cancer therapy applications of chiral supramolecular nanomaterials.(A) Photothermal nanodrugs with amino-acidencoded therapeutic activities.Reproduced with permission. [139]Copyright 2022, with permission from Wiley-VCH.(B) In vivo supramolecular coordination between Mn 2+ and hypericin (Hyp) induced cross-linking and enhanced photodynamic therapy efficacy.Reproduced with permission. [140]Copyright 2023, with permission from Wiley-VCH.PEI, polyethylenimine; UCNP, upconversion nanoparticles.allowed them to achieve enhanced photodynamic therapy (PDT) through in situ crosslinking induced by supramolecular coordination, triggered by the tumor microenvironment.The approach aims to enhance the therapeutic effect by maximizing the functions of individual components through internal or external stimulation, as depicted in Figure 10B.
Anionic polymers functionalized with carboxylic acid or benzoic acid were synthesized by Leong et al. [141] These polymers were then successfully utilized for the selfassembly of nanocomplexes with the anticancer polymer pBu_20.The particles that were created had a size smaller than 200 nm.The creation of the NPs eliminated the favorable charges and enhanced the half-life and toxicity level (LD 50 ) of pBu_20 in living organisms.
To create a range of high-performance PSs, Tu et al. utilized a molecular engineering strategy on the building blocks of metallacycles, resulting in Ru II metallacyclebased PSs. [142]The efficiency of reactive oxygen species (ROS) production and biocompatibility could be enhanced by conducting detailed in vitro experiments and theoretical calculations, which confirmed the effectiveness of the optimized emissive ligand, electron-rich Ru II acceptor, and sterically bulky ligand.
Hu et al. suggested a supramolecular approach for drug delivery, aiming to simultaneously transport nitric oxide (NO) and a photothermal agent based on an AIE called aggregation-induced emission (AIE)-featured photosensitizer. [143]This strategy is designed for mild-temperature PTT potentiated by ONOO − .The drug nanocarriers exhibited a round shape with a hydrodynamic size of approximately 100 nm.The study uncovers a fresh use case for ONOO − and presents a groundbreaking approach to decrease the heat resistance of malignant cells.This holds great potential for hyperthermia-centered cancer treatment methods, like, PTT and radiofrequency ablation.

| Wound repair
The healing of a cutaneous wound encompasses four distinct stages that exhibit overlapping characteristics: hemostasis, inflammation, proliferation, and maturation.[146][147] Nonhealing chronic wounds are formed when the orderly phases of wound healing are not successfully transitioned from the inflammatory to the proliferative phase, which is a critical step in the process. [148]en et al. developed a novel antibacterial hydrogel with self-repairing properties. [149]This hydrogel was made from a biodegradable derivative of poly(aspartic acid) (PASP), which contained a functional group of phenylboronic acid and quaternary ammonium.The hydrogel has the ability to adhere to the skin and control the surrounding environment of the wound, thus preventing infections.Additionally, the hydrogel loaded with mouse epidermal growth factor can enhance the healing process of the wounds, as shown in Figure 11A.Consequently, the antibacterial hydrogel derived from PASP with the ability to self-repair has significant potential in the fields of bioscience and biotechnology.This includes its use in delivering antitumor drugs, tissue engineering, and most notably, wound healing.Chen et al. disclosed a method to address chronic wounds in diabetic patients by utilizing a nanoconfined catalytic system, which achieves dual benefits. [150]The efficacy of the supramolecular cascade reaction process within the wound site, when restricted to the nanoscale, was confirmed through experiments conducted on living organisms.These experiments demonstrated that this process could effectively exhibit antibacterial properties while also providing wound protection via hydrogel (Figure 11B).Zhao et al. described a hydrogel formed by the selfassembly of the herbal compound rhein and a crosslinked network that responds to oxidation. [151]This network is based on the recognition between ferrocene and β-CDx.The hydrogel generated demonstrated efficacy in promoting the healing of chronic wounds through the suppression of excessive ROS.
A novel see-through conductive hydrogel, known as PVA-CEC-AGA/Ag (polyvinyl alcohol-N-carboxyethyl chitosan-agarose/Ag), was created by Zhao et al.It relies on a complex network structure formed by multiple hydrogen bonds. [152]According to in vivo findings, this hydrogel has the potential to successfully stimulate angiogenesis, boost collagen formation, safeguard against bacterial infection, and manage wound infection in animal models with diabetic foot ulcers, ultimately facilitating wound healing.

| Antibacterial
The attachment and establishment of bacteria on surfaces can give rise to significant issues, including implant infections, malfunctions of medical devices, and potential risks to public health.There has been a notable increase in academic investigations related to antibacterial surfaces, particularly within the realm of biomedical applications. [153,154] technique utilizing microfluidics was created by Schnaider et al. to produce hybrid silk-based microgels that exhibit robust antibacterial characteristics. [155]The combination of this ability, along with the compatibility of the silk microgels with living organisms, and the flexibility of this system, enable the use of this method for various applications in biotechnology and medicine (Figure 12A).Zhao et al. created hydrogels that possess quick shape adaptability, rapid self-repair, tissue adhesion, antioxidative properties, and responsiveness to NIR/pH stimuli. [156]hese hydrogels were developed using a prepolymer called poly(glycerol sebacate)-co-poly(ethylene glycol)-g-catechol and modified gelatin with UPy-hexamethylene diisocyanate synthon.The double-network hydrogel adhesives, which are physical in nature, serve as exceptional multifunctional dressings for the treatment of methicillin-resistant staphylococcus aureus infection, wound closure, and wound healing.These dressings can be easily removed when required (as shown in Figure 12B).By combining the distinct benefits of quaternized chitosan (QCS) and reduced graphene oxide, Zhang et al. developed a range of injectable self-repairing conductive supramolecular hydrogels using the host-guest interaction between CD and AD. [157]The QCS-CD-AD/GO supramolecular hydrogel that was acquired maintains its distinctive electrical characteristic, in addition to having suitable swelling, rheological, and exceptional photothermal properties.
subsequently leading to the induction of a robust immune response via the utilization of a suitable vaccine and/or immunostimulant.
In their research, Li et al. provided a comprehensive description of a supramolecular nanomedicine possessing three distinct functionalities. [162]These functionalities encompassed the incorporation of indoximod, a compound known for its ability to inhibit indoleamine 2,3-dioxygenase, a D-peptide antagonist (DPPA-1) specifically designed to target programmed cell death ligand-1, and a self-assembling D-tetrapeptide of GDFDFDY, which exhibited potent adjuvant properties and immunostimulatory effects.The findings of this research offer a hopeful approach to the creation of novel simultaneous drug combinations for tumor immunotherapy (as shown in Figure 13A).Xu et al. described an easy and direct approach for the synthesis and evaluation of a specific immunogenic peptide combined with AuNPs and integrated into a host-guest hydrogel system as an injectable therapeutic nanovaccine that can simultaneously deliver tumor antigen peptide and CpG for cancer immunotherapy. [163]By utilizing the hydrogel nanovaccine with tumor-specific peptides, it is possible to induce potent T-cell responses against tumor antigens in mice with malignant melanoma, ultimately leading to a successful antitumor immunotherapy outcome (Figure 13B).Shi et al. devised a technique to enhance the surface properties of natural killer (NK) cells by attaching extremely effective polyvalent antibody mimics (PAMs).PAM-modified NK cells exhibit superior ability to identify and attach to cancerous cells compared with their natural or monovalent antibody mimic-modified counterparts. [164]iu et al. effectively highlighted the production of chiral-nano vaccines (L/D-OVA) through the use of chiral cyclodextrins (CDs) as carriers and immune adjuvants. [165]he antigen model employed in this study was ovalbumin (OVA).The internalization of L/D-OVA nano vaccines by mouse bone-marrow-derived dendritic cells (BMDCs) was found to be effective in promoting BMDC maturation, facilitating efficient cross-presentation to T cells, and inhibiting the growth of B16-OVA melanoma.This study showcases the potential of chiral CDs as effective vehicles for encapsulating protein payloads and facilitating their delivery into cancer cells.

| Antimicrobial
In recent years, there has been an emerging trend towards the implementation of material-centric approaches in the management of bacterial infections. [166]hese techniques have provided an approach to achieve the desired therapeutic result while mitigating the potential for the development of drug-resistant bacteria.

F I G U R E 14
The antimicrobial applications of chiral supramolecular nanomaterials.(A) Molecular components and antibiofilm activity of the MSNs.Reproduced with permission. [167]Copyright 2020, with permission from American Chemical Society.(B) Antibacterial properties of hydrogel.Reproduced with permission. [168]Copyright 2021, with permission from Wiley-VCH.ADA, adamantane; AHAM, N- et al. exhibited the uncomplicated self-organization of a positively charged porphyrin (Pp4N) and GNRPEO2000, resulting in a novel nanocomposite that integrates both PDT and PTT capabilities to combat bacterial infections. [169]The current findings emphasize the potential of combining various therapeutic mechanisms to improve the effectiveness of antimicrobial materials.Therefore, the application of this method in new systems may be beneficial in meeting the increasing demand for alternative agents to antibiotics.
The "host defense system" (HDS) was developed by Yi et al. to treat bacterial infections. [170]Initially, the HDS has the ability to rapidly ensnare the bacteria through electrostatic attractions.Furthermore, the system has the capability to generate substantial quantities of cytotoxic ROS and exert potent antibacterial properties, thereby facilitating the modulation of the immune microenvironment.This modulation ultimately results in the transformation of macrophages from an M0 state to a proinflammatory phenotype (M1), which effectively collaborates in the eradication of bacteria.
Sun et al. created a group of diblock copolypeptoids (poly(N-allylglycine)-g-NH 2 )-b-poly(N-octylglycine) through ring-opening polymerization and postpolymerization functionalization. [171]The copolypeptoids exhibit the capacity to undergo self-assembly into both fibrous and spherical micellar structures in aqueous environments, which is influenced by the pH conditions.The assemblies demonstrate remarkable antimicrobial efficacy due to the presence of amine groups.

| CONCLUSIONS
The field of chiral supramolecular nanomaterials is highly promising and stimulating, particularly with regard to selfassembly at both the molecular and supramolecular scales.Supramolecular chirality refers to the interactions between constituent molecules in self-assembled structures.The successful transmission of chirality from a chiral component to the entire assembly is of paramount importance in this context, as it determines the overall chirality of the system.Furthermore, it is possible to induce supramolecular chirality through symmetry breaking, even in the absence of chiral molecules.This review has examined various instances of the manifestation and manipulation of supramolecular chirality, in addition to its distinctive attributes and functions.
However, despite these insights, there remain a multitude of unresolved inquiries pertaining to supramolecular chirality.Commencing the discussion, the anticipation of molecular assembly and the chirality of supramolecular architectures is a challenging task.The utilization of time-dependent density functional theory computations to anticipate the chiral assembly presents a captivating opportunity to advance our understanding of chiral hydrogels.The deficiency in mechanical robustness exhibited by chiral supramolecular hydrogels poses a significant limitation to their practical utility.
The initial studies demonstrated the promising capabilities of chiral supramolecular nanomaterials in various applications, such as biosensing, bioimaging, drug/gene delivery, and therapeutics.There is a significant demand for the translation from bench-to-bedside in the field of biomedical applications.The investigation into the novel capabilities of established chiral supramolecular nanomaterials is of utmost importance, necessitating the cooperation of experts from diverse disciplines, such as supramolecular chemistry, chemical biology, life sciences, pharmacy, and medicine.
To advance the research, it will be necessary to implement in situ chirality modification techniques.The utilization of this methodology may be implemented to examine the kinetic impacts of the extracellular chiral microenvironment on biological entities.The investigation could potentially yield insights into the physiological mechanisms underlying supramolecular helical configurations in biological systems.It is believed that a multitude of novel techniques can still be achieved by utilizing existing molecules.The intrinsic correlation between molecular structures and functions can be succinctly summarized, thereby providing guidance for the development of novel chiral supramolecular derivatives.It is anticipated that in the foreseeable future, the field of chiral supramolecular nanomaterials will yield substantial advantages for humanity, owing to ongoing research and development endeavors.The main goal of this review is to promote the progress and regulation of chirality in supramolecular chiral networks that exhibit considerable potential for various applications.

ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (Grant numbers 21975191 and 52273110), the Natural Science Foundation of Hubei Province (Grant number 2021CFB299), the Knowledge Innovation Program of Wuhan-Shuguang Project (GGB), the Youth Innovation Fund of State Key Laboratory of Advanced Technology for Materials Synthesis and Processing (GGB), and Fundamental Research Funds for the Central Universities (WUT) (Grant number 2021III035JC).

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

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I G U R E 13 The immune applications of chiral supramolecular nanomaterials.(A) Chemical structures of IND-GFFY, IND-GDFDFDY, and hydrogel formation.Reproduced with permission.