Photoresponsive protamine ionic complex towards a smart hemostatic biomaterial.

Protamine (PA) is the only licensed antidote for reversing heparin anticoagulation by electrostatically binding with heparin. Efforts have been made on designing various heparin-scavengers, while, it remains a great challenge for gaining the external-stimuli responsive PA-release material. In this study, a generic strategy is developed for fabricating photoresponsive protein materials with the designed azobenzene-containing surfactant. For the first time, based on the isomerization of azobenzene, both cationic and anionic proteins could be phase change biomaterials which are capable of transiting to isotropic state under UV irradiation at room temperature. The formation of isotropic state could set the proteins free from the binding state, activating their intrinsic biological functions. Employing this mechanism, one smart PA material for inhibiting heparin is developed, which could effectively photo-modulate the heparin concentration by turning on-and-off the free state of PA from the binding state. With good biocompatibility, the PA material addresses photoresponsive hemostatic activity in biological studies, confirming its great potential clinical values. This work provides a new designing strategy for gaining photocontrollable hemostasis materials, also opening new opportunities for developing photoresponsive protein drugs and biomedical materials.

Light-Responsive Smart Nanoliposomes: Harnessing the Azobenzene Moiety for Controlled Drug Release under Near-Infrared Irradiation.

The azobenzene moiety is an intriguing structure that deforms under UV and visible light, indicating a high potential for biomedical applications. However, its reaction to UV radiation is problematic because of its high energy and low tissue penetration. Unlike previous research on azobenzene structures in photoresponsive materials, this study presents a novel method for imparting photostimulation-responsive properties to liposomes by incorporating the azobenzene moiety and extending the light wavelength with up-conversion nanoparticles. First, the azobenzene structure was incorporated into a phospholipid molecule to create Azo-PSG, which could spontaneously form vesicle assemblies in aqueous solutions and isomerizes within 1 h of light exposure. Furthermore, orthogonal up-conversion nanoparticles with a core-shell structure were created by sequentially growing lanthanide rare earths in the shell layer, which efficiently converts near-infrared light into ultraviolet (400 nm) and blue-green (540 nm) light. Combining these core-shell structured up-conversion nanomaterials with Azo-PSG molecules resulted in the creation of a near-infrared light-responsive smart nanoliposome system. Under near-infrared light irradiation, UCNPs emit UV and blue-green light, causing conformational changes in Azo-PSG molecules that allow drug release within 6 h. The reversible structural shift of Azo-PSG in response to light stimulation holds enormous promise for improving drug release techniques. This novel technique also expands the usage of UV-responsive compounds beyond their constraints of low penetration and high biotoxicity, allowing for rapid medication release under NIR light.

Main-Chain Azobenzene Poly(ether ester) Multiblock Copolymers for Strong and Tough Light-Driven Actuators.

The stimulus-responsive polymeric materials have attracted great research interest, especially those remotely manipulated materials with potential applications in actuators and soft robotics. Here we report a photoresponsive main-chain actuator based on azobenzene poly(ether ester) multiblock copolymer (mBCP) thermoplastic elastomers, (PTAD-b-PTMO-b-PTAD)n, which were synthesized by a cascade polycondensation-coupling ring-opening polymerization method using poly(tetramethylene oxide) (PTMO) and azobenzene-containing cyclic oligoesters (COTADs) as monomers. The thermal, mechanical, and microphase separation behaviors of mBCPs could be flexibly tuned by altering the ratios of soft-to-hard segments and block number (n). The oriented azobenzene mBCP fibers were prepared by melt spinning, showing reversible photoresponsive properties with remarkably high strength (∼1000 MPa) and high elongation at break comparable to spider silks. Fast photoinduced bending and contraction were successfully achieved in these fibers with high work and power densities and energy conversion efficiency, enabling it to lift up about 250 times of its own weight. Moreover, it can take out materials inside the tube by UV-light control. These fibers could be applied in light-driven actuators or telecontrolled robot arms.

Engineering the novel azobenzene-based molecular photoswitches for suppressing bacterial infection through dynamic regulation of biofilm formation.

BACKGROUND: Bacterial biofilm is a strong fortress for bacteria to resist harsh external environments, which can enhance their tolerance and exacerbate the drug/pesticide resistance risk. Currently, photopharmacology provides an advanced approach via precise spatiotemporal control for regulating biological activities by light-controlling the molecular configurations, thereby having enormous potential in the development of drug/pesticides. RESULTS: To further expand the photopharmacology application for discovering new antibiofilm agents, we prepared a series of light-controlled azo-active molecules and explored their photo isomerization, fatigue resistance, and anti-biofilm performance. Furthermore, their mechanisms of inhibiting biofilm formation were systematically investigated. Overall, designed azo-derivative A11 featured excellent anti-Xoo activity with an half-maximal effective concentration (EC50) value of 5.45 µg mL-1, and the EC50 value could be further elevated to 2.19 µg mL-1 after ultraviolet irradiation (converted as cis-configuration). The photo-switching behavior showed that A11 had outstanding anti-fatigue properties. An in-depth analysis of the action mechanism showed that A11 could effectively inhibit biofilm formation and the expression of relevant virulence factors. This performance could be dynamically regulated via loading with private light-switch property. CONCLUSION: In this work, designed light-controlled azo molecules provide a new model for resisting bacterial infection via dynamic regulation of bacterial biofilm formation. © 2024 Society of Chemical Industry.

Being Smarter, Azobenzene-Containing Biomaterial Showing Triple Stimuli-Responsive Phase Change Property to Light, Humidity and Force at Room Temperature.

Multiple stimuli-responsiveness is an attractive property that is studied in physical chemistry and materials chemistry. While, multiple stimuli-responsive phase change in an isothermal way is rarely addressed for functional materials at room temperature. In this study, one azobenzene-containing surfactant AZO is designed for the fabrication of triple stimuli-responsive phase change biomaterial (Alg-AZO) through the electrostatic complexation with natural alginate. Thanks to the photoisomerization ability, molecular flexibility and hydrophilicity of AZO, together with the tailoring effect of alginate on AZO, Alg-AZO could perform reversible isothermal phase transition between liquid crystalline and isotropic liquid states under the stimuli of either light or humidity at room temperature. Furthermore, the humidity-induced isotropic state can also fast transit to ordered state under shear force, owing to the π-π interactions between planar trans-AZO in Alg-AZO material. With good biocompatibility, self-healing property and in vivo wound healing promoting capacity that is promoted by light, humidity and force, Alg-AZO would be suitable for working as a new smart biomaterial in biological and biomedical areas. This work provides a designing strategy for gaining multiple stimuli-responsive smart materials based on biomacromolecules, and also opening a new opportunity for gaining self-healing biomaterials capable of working in various conditions.

Clay Nanosheet-Based Nanocomposite Supramolecular Hydrogel Enabling Rapid, Reversible Phase Transition Only with Visible Light.

High mechanical properties and rapid sol/gel phase transition are mutually exclusive in the hydrogels reported to date, most likely because the 3D crosslinked networks of mechanically robust hydrogels comprise bundled thick fibers that are not rapidly dissociable or formable.  Herein, we report a visible light-responsive hydrogel that showed a rapid, reversible sol/gel phase transition despite its relatively high mechanical properties (storage modulus ~1000 Pa).  To construct its 3D crosslinked network, we used a design strategy analogous to that employed for our highly water-rich yet mechanically robust nanocomposite supramolecular hydrogel ("aqua material").  In this case, multiple poly(ethylene glycol) chains carrying ortho-tetramethoxyazobenzene termini (AzoPEG) were noncovalently crosslinked by clay nanosheets (CNSs) with surface-immobilized ß-cyclodextrin units using their seven guanidinium ion (Gu+) pendants (GuCD) via a multivalent salt-bridge.  When exposed to visible light at 625 and 450 nm, the azobenzene termini isomerized from trans-to-cis and cis-to-trans, respectively, and were detached from and attached to the surface-immobilized GuCD units.  The advantage of this CNS-based nanocomposite supramolecular system is its simple 3D network structure, which forms and breaks rapidly without slow chain entangling and disentangling processes.

Tuning the Thermal Stability of Tetra-o-chloroazobenzene Derivatives by Transforming Push-Pull to Push-Push Systems.

Molecular photoswitches provide interesting tools to reversibly control various biological functions with light. Thanks to its small size and easy introduction into the biomolecules, azobenzene derivatives have been widely employed in the field of photopharmacology. All visible-light switchable azobenzenes with controllable thermostability are highly demanded. Based on the reported tetra-o-chloroazobenzenes, we synthesized push-pull systems, by introducing dialkyl amine and nitro groups as strong electron-donating and electron-withdrawing groups on the para-positions, and then transformed to push-push systems by a simple reduction step. The developed push-pull and push-push tetra-o-chloroazobenzene derivatives displayed excellent photoswitching properties, as previously reported. The half-life of the Z-isomers can be tuned from milliseconds for the push-pull system to several hours for the push-push system. The n-π* and π-π* transitions have better resolution in the push-push molecules, and excitation at different wavelengths can tune the E/Z ratio at the photostationary state. For one push-pull molecule, structure and absorption spectra obtained from theoretical calculations are compared with experimental data, along with data on the push-push counterpart.

Recent trends and future perspectives of photoresponsive-based mercury (II) sensors and their biomaterial applications.

Recent advancements in the field of photoresponsive-based mercury (II) sensors have witnessed a surge in research focused on enhancing detection capabilities. Leveraging innovations in materials science, particularly with quantum dots, nanomaterials, and organic semiconductors, these sensors exhibit improved selectivity and sensitivity. Beyond traditional applications, such as environmental monitoring, the integration of photoresponsive principles with emerging technologies like the internet of things (IoT) and wearable promises real-time and remote mercury (II) ion detection. The on-going efforts also explore multifunctional sensors and miniaturization for on-site applications, addressing current challenges and paving the way for broader commercialization. This dynamic landscape underscores the potential for these sensors to play a crucial role in ensuring the effective monitoring and management of mercury (II) levels in diverse settings.

Azobenzene-attached (NHC)Gold(I) and (NHC)Copper(I) Complexes as Photoswitchable Catalysts.

Photoswitchable (pre)catalysts, N,N'-bis-azobenzene-based (NHC)gold(I) and N,N'-bis-azobenzene-derived (NHC)copper(I) complexes are reported. Trans to cis isomerization of the attached photoswitchable moieties in the Au(I) complex enables four-fold decrement in the rate of oxazoline formation reaction. Whereas the progress of the copper(I) catalyzed, azide-alkyne cycloaddition reaction gets reduced by at least threefold. Alternate exposure to UV and blue light could easily toggle the rate of reactions remotely. The catalytic activity of thermodynamically stable trans-trans isomers is found to be similar to the common N-aryl substituted NHC-Au/Cu(I) complexes. NHC-Au(I) and -Cu(I) compounds bearing (trans)azobenzene moieties were characterized by X-ray diffraction. Photoswitching, recyclability studies, and the metastable isomer's thermal half-life in both complexes were studied via UV-visible spectroscopy. Whereas the extent of photoswitching and concomitant formation of geometrical isomers were investigated by using 1H-NMR spectroscopic study. Calculated percentage buried volumes of the three geometrical isomers show the trend trans-trans < trans-cis < cis-cis.

Azobenzene-based liposomes with nanomechanical action for cytosolic chemotherapeutic drug delivery.

The stimuli-responsive nano-carriers are at the forefront of research in nanotechnology and materials science. These advanced systems are designed to alter their physicochemical properties upon exposure to specific stimuli, enabling controllable and targeted delivery of therapeutic agents. Nevertheless, limited endosomal escape reduces the drug bioavailability in clinical use. We herein report azobenzene (Azo)-based liposomes, prepared by co-assembling the photoisomerizable cationic Azo lipids and helper lipids, which achieve controllable doxorubicin (Dox) release and enhanced cytosolic transport upon light irradiation. Azo lipids undergo reversible isomerization between cis-isomers and trans-isomer when received UV and visible (Vis) light irradiation, causing liposomal membrane permeability changes for controlled drug release. Moreover, the nanomechanical action created by the isomerization of Azo lipids promotes the endosomal escape of the liposomes. DSPC-Azo liposomes, with minimal Dox leakage, showed significant tumor cell killing upon irradiation. For in vivo study, we co-encapsulated the upconverting nanoparticles (UCNPs), which can convert the near-infrared (NIR) light into UV/Vis emissions, facilitating Azo units activation. UCNP/Dox-loaded DSPC-Azo liposomes inhibited tumor growth under NIR irradiation in a 4T1 tumor-bearing mouse model.

Regeneratable bioinspired nanochannels for highly sensitive electrochemical detection of glycated albumin.

Glycated albumin (GA) has been proposed as a reliable diabetes mellitus marker particularly useful in assessing intermediate glycemic control. Herein, we designed a bioinspired nanochannels for biochemical detection based on the host-guest interaction between ß-cyclodextrin and azobenzene. Cyclodextrin was grafted on the inner surface of nanochannels of a nanoporous membrane and azobenzene was tagged to the terminal of GA aptamer, thereby facilitating the orientation of GA aptamer in the nanochannels. The presence of GA was monitored by recording the voltammetric signal of ferricyanide that transported across the nanochannel array. The peak current exhibited a linearity relationship with the GA concentration across a broad range of 1.0 ng mL-1 to 100 µg mL-1, along with a detection limit of 0.18 ng mL-1. Notably, the aptamer could be offloaded under ultraviolet light, regenerating the cyclodextrin functionalized nanochannels for subsequent re-immobilization of the fresh aptamer. The relative standard deviation for seven cycles of regeneration treatment was no more than 1.8 %. The remarkable reusability of the nanochannels offered a cost-effective, sensitive and reproducible aptasensing platform.

Recent Advances of Light/Hypoxia-Responsive Azobenzene in Nanomedicine Design.

Azobenzene (Azo) and its derivatives are versatile stimuli-responsive molecules. Their reversible photoisomerization and susceptibility to reduction-mediated cleavage make them valuable for various biomedical applications. Upon exposure to the UV light, Azo units undergo a thermodynamically stable trans-to-cis transition, which can be reversed by heating in the dark or irradiation with visible light. Additionally, the N=N bonds in azobenzenes can be cleaved under hypoxic conditions by azoreductase, making azobenzenes useful as hypoxia-responsive linkers. The integration of azobenzenes into nanomedicines holds promise for enhancing therapeutic efficacy, particularly in tumor targeting and controllable drug release. In this Concept paper, recent advances in the design and applications of azobenzene-based nanomedicines are updated, and future development opportunities are also summarized.

An Innovative Azobenzene-Based Photothermal Fabric with Excellent Heat Release Performance for Wearable Thermal Management Device.

Azobenzene (azo)-based photothermal energy storage systems have garnered great interest for their potential in solar energy conversion and storage but suffer from limitations including rely on solvents and specific wavelengths for charging process, short storage lifetime, low heat release temperature during discharging, strong rigidity and poor wearability. To address these issues, an azo-based fabric composed of tetra-ortho-fluorinated photo-liquefiable azobenzene monomer and polyacrylonitrile fabric template is fabricated using electrospinning. This fabric excels in efficient photo-charging (green light) and discharging (blue light) under visible light range, solvent-free operation, long-term energy storage (706 days), and good capacity of releasing high-temperature heat (80-95 °C) at room temperature and cold environments. In addition, the fabric maintains high flexibility without evident loss of energy-storage performance upon 1500 bending cycles, 18-h washing or 6-h soaking. The generated heat from charged fabric is facilitated by the Z-to-E isomerization energy, phase transition latent heat, and the photothermal effect of 420 nm light irradiation. Meanwhile, the temperature of heat release can be personalized for thermal management by adjusting the light intensity. It is applicable for room-temperature thermal therapy and can provide heat to the body in cold environments, that presenting a promising candidate for wearable personal thermal management.

Synthesis, mol-ecular and crystal structures of 4-amino-3,5-di-fluoro-benzo-nitrile, ethyl 4-amino-3,5-di-fluoro-benzoate, and diethyl 4,4'-(diazene-1,2-di-yl)bis-(3,5-di-fluoro-benzoate).

The crystal structures of two inter-mediates, 4-amino-3,5-di-fluoro-benzo-nitrile, C7H4F2N2 (I), and ethyl 4-amino-3,5-di-fluoro-benzoate, C9H9F2NO2 (II), along with a visible-light-responsive azo-benzene derivative, diethyl 4,4'-(diazene-1,2-di-yl)bis-(3,5-di-fluoro-benzoate), C18H14F4N2O4 (III), obtained by four-step synthetic procedure, were studied using single-crystal X-ray diffraction. The mol-ecules of I and II demonstrate the quinoid character of phenyl rings accompanied by the distortion of bond angles related to the presence of fluorine substituents in the 3 and 5 (ortho) positions. In the crystals of I and II, the mol-ecules are connected by N-H⋯N, N-H⋯F and N-H⋯O hydrogen bonds, C-H⋯F short contacts, and π-stacking inter-actions. In crystal of III, only stacking inter-actions between the mol-ecules are found.

Reversible Solubility Switching of a Polymer Triggered by Visible-Light Responsive Azobenzene Photochromism with Negligible Thermal Relaxation.

This study reports the reversible solubility switching of a polymer triggered by non-phototoxic visible light. A photochromic polymerizable azobenzene monomer with four methoxy groups at the ortho-position (mAzoA) was synthesized, exhibiting reversible photoisomerization between trans- and cis-states using green (546 nm) and blue light (436 nm). Free radical copolymerization of hydrophilic dimethylacrylamide (DMAAm) with mAzoA produced a light-responsive random copolymer (P(mAzoA-r-DMAAm)) that shows a reversible photochromic reaction to visible light. Optimizing mAzoA content resulted in P(mAzoA10.7-r-DMAAm)3.0 kDa exhibiting LCST-type phase separation in PBS (pH 7.4) with trans- and cis-states at 39.2 °C and 32.9 °C, respectively. The bistable temperature range of 6.3 °C covers 37 °C, suitable for mammalian cell culture. Reversible solubility changes were demonstrated under alternating green and blue light at 37 °C. 1H NMR indicated significant retardation of thermal relaxation from cis- to trans-states, preventing undesired thermal mechanical degradation. Madin Darby Canine Kidney (MDCK) cells adhered to the P(mAzoA-r-DMAAm) hydrogel, confirming its non-cytotoxicity and potential for biocompatible interfaces. This principle is useful for developing hydrogels that can reversibly stimulate cells mechanically or chemically in response to visible light.

Enhanced Photodynamic Therapy for Neurodegenerative Diseases: Development of Azobenzene-Spiropyran@Gold Nanoparticles for Controlled Singlet Oxygen Generation.

The development of durable photosensitizers is pivotal for advancing phototherapeutic applications in biomedicine. Here, we introduce a core-shell azobenzene-spiropyran structure on gold nanoparticles, engineered to enhance singlet oxygen generation. These nano-photosensitizers exhibit increased structural stability and thermal resistance, as demonstrated by slowed O-N-C bond recombination dynamics via in-situ Raman spectroscopy. Notably, the in-situ formation of merocyanine and a light-induced compact shell arrangement extend its half-life from 47 minutes to over 154 hours, significantly boosting singlet oxygen output. The nano-photosensitizer also shows high biocompatibility and notably inhibits tau protein aggregation in neural cells, even with phosphatase inhibitors. Further, it promotes dendritic growth in neuro cells, doubling typical lengths. This work not only advances chemical nanotechnology but also sets a foundation for developing long-lasting phototherapy agents for treating neurodegenerative diseases.

Understanding X-ray-induced isomerisation in photoswitchable surfactant assemblies.

Dynamic, responsive materials can be built using photosurfactants (PS) that self-assemble into ordered nanostructures, such as micelles or liquid crystals. These PS contain photoswitchable groups, such as azobenzene (Azo) or, more recently, arylazopyrazoles (AAPs), which change shape and polarity on photoisomerisation between the E and Z states, thus changing the self-assembled structure. Small-angle X-ray scattering (SAXS) is a powerful technique to probe the morphology of PS and can be used to measure the mechanisms of structural changes using in-situ light irradiation with rapid, time-resolved data collection. However, X-ray irradiation has been shown previously to induce Z-to-E isomerisation of Azo-PS, which can lead to inaccuracies in the measured photostationary state. Here, we investigate the effect of light and X-ray irradiation on micelles formed from two different PS, containing either an Azo or AAP photoswitch using SAXS with in-situ light irradiation. The effect of X-ray irradiation on the Z isomer is shown to depend on the photoswitch, solvent, concentration and morphology. We use this to create guidelines for future X-ray experiments using photoswitchable molecules, which can aid more accurate understanding of these materials for application in solar energy storage, catalysis or controlled drug delivery.

Exciting Novel Polyaspartates: Design, Synthesis, and Photo-Responsive Behavior in Solution and Lyotropic Liquid Crystalline Phase Upon Irradiation with Visible Light.

Many polypeptides form stable, helical secondary structures enabling the formation of lyotropic liquid crystalline (LLC) phases. Contrary to the well-studied polyglutamate, their counterparts based on polyaspartates exhibit a much lower helix inversion barrier. Therefore, the helix sense is not solely dictated by the chirality of the amino acid used, but additionally by the nature and conformation of the polymer sidechain. In this work, polymers responsive to irradiation with visible light are designed achieving conformational transitions from helix-to-coil and helix-to-helix. The synthesis and the application as LLC mesogens of several (co-)polyaspartates bearing ortho-fluorinated azobenzene (FAB) as a photochromic group are presented. Many of the obtained polymers undergo changes in their secondary structure upon E-Z-isomerization of the FAB-containing sidechain. Of special interest are copolymers that exhibit photo-responsive helix inversion without loss of their helical secondary structure. These copolymers form stable LLC phases in helicogenic solvents, where the effect of photo-switching on the macroscopic behavior is studied by NMR spectroscopy. Especially, the irradiation of the different LLC phases of the helix inversion polymers displays a change in the LLC order experienced by the solvent. These peculiar properties are promising for future applications as photo-responsive alignment media for structure elucidation in NMR.

Transient Photoactivation of Anionophores by Using Redshifted Fast-Relaxing Azobenzenes.

Photo-regulated transmembrane ionophores enable spatial and temporal control over activity, offering promise as targeted therapeutics. Key to such applications is control using bio-compatible visible light. Herein, we report red-shifted azobenzene-derived synthetic anionophores that use amber or red light to trigger (E)-(Z) photoisomerisation and activation of transmembrane chloride transport. We demonstrate that by tuning the thermal half-life of the more active, but thermodynamically unstable, Z isomer to relax on the timescale of minutes, transient activation of ion transport can be achieved by activating with solely with visible light and deactivating by thermal relaxation.

Robust Multifunctional Ultrathin 2 Nanometer Organic Nanofibers.

Ultrathin organic nanofibers (UTONFs) represent an emerging class of nanomaterials as they carry a set of favorable attributes, including ultrahigh specific surface area, lightweight, and mechanical flexibility, over inorganic counterparts, for use in biomedicine and nanotechnology. However, precise synthesis of uniform UTONFs (diameter ≤ 2 nm) with tailored functionalities remained challenging. Herein, we report robust multifunctional UTONFs using hydrophobic interaction-driven self-assembly of amphiphilic alternating peptoids containing hydrophobic photoresponsive azobenzene and hydrophilic hydroxyl moieties periodically arranged along the peptoid backbone. Notably, the as-crafted UTONFs are approximately 2 nm in diameter and tens of micrometers in length (an aspect ratio, AR, of ∼10000), exemplifying the UTONFs with the smallest diameter yielded via self-assembly. Intriguingly, UTONFs were disassembled into short-segmented nanofibers and controllably reassembled into UTONFs, resembling "step-growth polymerization". Photoisomerization of azobenzene moieties leads to reversible transformation between UTONFs and spherical micelles. Such meticulously engineered UTONFs demonstrate potential for catalysis, bioimaging, and antibacterial therapeutics. Our study highlights the significance of the rational design of amphiphiles containing alternating hydrophobic and hydrophilic moieties in constructing otherwise unattainable extremely thin UTONFs with ultrahigh AR and stimuli-responsive functionalities for energy and bionanotechnology.