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Noninvasive control over the reversible generation of singlet oxygen (1O2) has found the enormous practical implications in the field of biomedical science. However, metal-free pure organic emitters, connected with a photoswitch, capable of generating "on-demand" 1O2 via triplet harvesting remain exceedingly rare; therefore, the utilization of these organic materials for the reversible control of singlet oxygen production remains at its infancy. Herein, an ambient triplet mediated emission in quinoline-dithienylethene (DTE)-core-substituted naphthalene diimide (cNDI) derivative is unveiled via delayed fluorescence. The quinoline-DTE-cNDI triad displayed enhanced photoswitching efficiency via double FRET mechanism.  It was found to have direct utilization in controlled photosensitized organic transformations via efficient generation of singlet oxygen (yield ΦΔ ~ 0.73). The designed molecule exhibits a long-lived emission (τ ∼ 1.1 µs) and very small singlet-triplet splitting (ΔSET) of 0.13 eV empowering it to display delayed fluorescence. Comprehensive steady state and time-resolved emission spectroscopy (TRES) analyses along with DFT calculations offer detailed understandings into the excited-state manifolds of organic compound and energy transfer (ET) pathways involved in 1O2 generation.

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In this work, we used DFT and TD-DFT in the investigation of the structural parameters and photophysics of the complex [Ru(bpy)2dppn]2+ (dppn = benzo[i]-dipyrido[3,2- a:2',3'-c]phenazine) in water, and its suitability as a photosensitizer (PS) in photodynamic therapy (PDT). For that, the thermodynamics of electron transfer (ET) and energy transfer (ENT) reactions in the excited state with molecular oxygen and guanosine-5'-monophosphate (GMP) were investigated. The overall intersystem crossing (ISC) rate constant was approximately 1012 s-1, indicating that this process is highly favorable, and the triplet excited states are populated. The triplet excited states are known to lead to photoreactions between the PS and species of the medium or directly with nucleobases. Here, we show that the Rudppn complex can react favorably to oxidize the GMP and generate singlet oxygen. Furthermore, this complex can also act as an intercalator between DNA base pairs and undergo dual-channel reactions. It has been proposed that the T2 excited state is responsible for oxidizing the GMP, but we show that T1 is thermodynamically capable of undergoing the same reaction. In this sense, docking simulations were carried out to investigate further the interactions of the Rudppn complex with a DNA fragment.

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DNA phase separation participates in chromatin packing for the modulation of gene transcription, but the induction of DNA phase separation in living cells for disease treatment faces huge challenges. Herein, we construct a Ru(II)-polypyridyl-loaded upconversion nanoplatform (denoted as UCSNs-R) to achieve the manipulation of DNA phase separation and production of abundant singlet oxygen (1O2) for efficient treatment of gliomas. The utilization of the UCSN not only facilitates high loading of Ru(II)-polypyridyl complexes (RuC) but also promotes the conversion of near-infrared (NIR) laser to ultraviolet light for efficient 1O2 generation. The released RuC exhibit DNA "light-switch" behavior and high DNA binding affinity that induce phase separation of DNA in living cells, thus resulting in DNA damage and suppressing tumor-cell growth. In vivo investigation demonstrates the high capability of UCSNs-R in inhibiting tumor proliferation under NIR laser illumination. This work represents a paradigm for designing a DNA phase separation nanoinducer through integration of the UCSN with Ru(II)-polypyridyl-based complexes for efficient therapy of gliomas.

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Developing multifunctional, stimuli-responsive nanomedicine is intriguing because it has the potential to effectively treat cancer. Yet, poor tumor penetration of nanodrugs results in limited antitumor efficacy. Herein, an oxygen-driven silicon-based nanomotor (Si-motor) loaded with MnO and CaO2 nanoparticles is developed, which can move in tumor microenvironment (TME) by the cascade reaction of CaO2 and MnO. Under acidic TME, CaO2 reacts with acid to release Ca2+ to induce mitochondrial damage and simultaneously produces O2 and H2O2, when the loaded MnO exerts Fenton-like activity to produce ·OH and O2 based on the produced H2O2. The generated O2 drives Si-motor forward, thus endowing active delivery capability of the formed motors in TME. Meanwhile, MnO with glutathione (GSH) depletion ability further prevents reactive oxygen species (ROS) from being destroyed. Such TME actuated Si-motor with enhanced cellular uptake and deep penetration provides amplification of synergistic oxidative stresscaused by intracellular Ca2 + overloading, GSH depletion induced by Mn2+, and Mn2+ mediated chemodynamic treatment (CDT), leading to excellent tumor cell death. The created nanomotor may offer an effective platform for active synergistic cancer treatment.

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We reported herein the synthesis, characterization of hybrid conjugates composed of phthalimide (Phth) and acridine-1,8-diones (Acr) for optical and medical applications. For the synthetic procedure, a three-step synthetic strategy has been utilized. The optical properties of the examined 1,8-acridinedione-phthalimide connected molecules (AcrPhth 1-5) have been examined utilizing various spectroscopic techniques, e.g., steady-state absorption and fluorescence, and time-correlated single photon counting. The steady-state absorption studies showed that AcrPhth 1-5 absorbs the light in the UV and visible region. The fluorescence studies of AcrPhth 1-5 exhibited significant fluorescence quenching compared to the acridinedione control compounds (Acr 1-5) suggesting the occurrence of electron-transfer reactions from the electron donating acridinedione moiety (Acr) to the electron accepting phthalimide moiety (Phth). The rate and efficiency of the electron-transfer reactions were determined from the fluorescence lifetime measurements indicating the fast electron-transfer processes of the covalently connected AcrPhth 1-5 conjugates. Computational studies supported the intramolecular electron-transfer reaction of AcrPhth conjugates using ab initio B3LYP/6-311G methods. In the optimized structures, the HOMO was found to be entirely located on the Acr entity, while the LUMO was found to be entirely on the Phth entity. Further, the synthesized compounds were tested as photosensitizers for generating the singlet oxygen species, which is a key factor in the photodynamic therapy (PDT) applications. The nanosecond laser flash measurements enable us to detect the triplet-excited states of examined Acr and AcrPhth conjugates, determining the triplet quantum yields, and direct detecting the singlet oxygen in an accurate way. From this observation, the singlet quantum yields were found to be in the range of 0.12-0.27 (for Acr 1-5) and 0.07-0.19 (for AcrPhth 1-5 conjugates). The molecular docking studies revealed that compound AcrPhth 2 exhibited high binding affinity with for key genes (p53, TOP2B, p38, and EGFR) suggesting its potential as a targeted anticancer therapy.

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The delayed healing of infected wounds can be attributed to the increased production of reactive oxygen species (ROS) and consequent damages to vascellum and tissue, resulting in a hypoxic wound environment that further exacerbates inflammation. Current clinical treatments including hyperbaric oxygen therapy and antibiotic treatment fail to provide sustained oxygenation and drug-free resistance to infection. To propose a dynamic oxygen regulation strategy, this study develops a composite hydrogel with ROS-scavenging system and oxygen-releasing microspheres in the wound dressing. The hydrogel itself reduces cellular damage by removing ROS derived from immune cells. Simultaneously, the sustained release of oxygen from microspheres improves cell survival and migration in hypoxic environments, promoting angiogenesis and collagen regeneration. The combination of ROS scavenging and oxygenation enables the wound dressing to achieve drug-free anti-infection through activating immune modulation, inhibiting the secretion of pro-inflammatory cytokines interleukin-6, and promoting tissue regeneration in both acute and infected wounds of rat skins. Thus, the composite hydrogel dressing proposed in this work shows great potential for dynamic redox regulation of infected wounds and accelerates wound healing without drugs.

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Efflux pumps are active transporters, which allow the cell to remove toxic substances from within the cell including antibiotics and photosensitizer complexes. Efflux pump inhibitors (EPIs), chemicals that prevent the passage of molecules through efflux pumps, play a crucial role in antimicrobial effectiveness against pathogen. In this work, we studied the effect of EPI, namely, reserpine, on photodeactivation rate of pathogens when used with Ag NPs and methylene blue (MB). Our results show that using reserpine led to a higher deactivation rate than Ag NPs and MB alone. The mechanism of this observation was investigated with singlet oxygen generation amount. Additionally, different sizes of Ag NPs were tested with reserpine. Molecular docking calculation shows that reserpine had higher affinity toward AcrB than MB. The improvement in bacterial deactivation rate is attributed to blockage of the AcrAB-TolC efflux pump preventing the removal of MB rather than enhanced singlet oxygen production. These results suggest that using reserpine with nanoparticles and photosynthesize is a promising approach in photodynamic therapy.

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Photoswitching materials have emerged as a promising class of compounds that possess manifold interesting properties rendering their widespread use from photoswitches, regulators to optoelectronic devices, security technologies and biochemical assays. Diarylethenes (DAE) constitute one such category of photoswitchable compounds, where the key features of stability, photoisomerization wavelengths, quantum yield and variability in the photoisomers significantly depend on their derivatization. The last decade has witnessed a surge in the engagement of DAEs in different areas of chemical and biological sciences, like biomarkers, controlled generation of singlet oxygen, photo-dynamic therapy, chemosensing, catalysis, etc. In all the cases, the photoswitchability of DAE is the principal regulating factor along with its emission properties according to the appended groups. Previous reviews on applications of DAE-based systems did not predominantly cover all the aspects of biological and industrial implementations. They have covered only one field of application either in the biological science or in the synthetic aspect or photochromic aspects only. This review is a coalition of all those aspects in last six years. Here the variation of properties of the DAE systems with respect to structural diversifications have been discussed in detail along with their potential applications in bioimaging of cells, regulating singlet oxygen generation for photodynamic therapy and catalysis of organic reactions, and their future prospects. A tabular presentation of the photophysical properties of DAE derivatives adds to the basic understanding of this subject at a glance. We hope that this cumulative collection of contemporary research on DAE, as presented in this review, will enhance the knowledge of the readers about synthetic design anticipating their properties well in advance, and will certainly motivate researchers to generate new DAE architectures with superior chemical and biological properties in future.

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Amultifunctional liposomal polydopamine nanoparticle (MPM@Lipo) was designed in this study, to combine chemotherapy, photothermal therapy (PTT) and oxygen enrichment to clear hyperproliferating inflammatory cells and improve the hypoxic microenvironment for rheumatoid arthritis (RA) treatment. MPM@Lipo significantly scavenged intracellular reactive oxygen species and relieved joint hypoxia, thus contributing to the repolarization of M1 macrophages into M2 phenotype. Furthermore, MPM@Lipo could accumulate at inflammatory joints, inhibit the production of inflammatory factors, and protect cartilage in vivo, effectively alleviating RA progression in a rat adjuvant-induced arthritis model. Moreover, upon laser irradiation, MPM@Lipo can elevate the temperature to not only significantly obliterate excessively proliferating inflammatory cells but also accelerate the production of methotrexate and oxygen, resulting in excellent RA treatment effects. Overall, the use of synergistic chemotherapy/PTT/oxygen enrichment therapy to treat RA is a powerful potential strategy.

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A series of porous organic polymers based on a singlet oxygen generating oxoporphyinogen ('OxP') has been successfully prepared from a pseudotetrahedral OxP-tetraamine precursor (OxP(4-NH2Bn)4) by its reaction with tetracarboxylic acid dianhydrides under suitable conditions. Of the compounds studied, those containing naphthalene (OxP-N) and perylene (OxP-P) spacers, respectively, have large surface areas (~530 m2 g-1). On the other hand, the derivative with a simple benzene spacer (OxP-B) exhibits the best 1O2 generating capability. Although the starting OxP-tetraamine precursor is a poor 1O2 generator, its incorporation into OxP POPs leads to a significant enhancement of 1O2 productivity, which is largely due to the transformation of NH2 groups to electron-withdrawing diimides. Overall 1O2 production efficacy of OxP-POPs under irradiation by visible light is significantly improved over the common reference material PCN-222. All the materials OxP-B, OxP-N and OxP-P promote oxidation of thioanisole involving conversion of ambient triplet state oxygen to singlet oxygen under visible light irradiation and its reaction with the sulfide. Although the reaction rate of the oxidation promoted by OxP POPs is generally lower than for conventional materials (such as PCN-222) or previously studied OxP derivatives, undesired overoxidation of the substrate to methyl phenyl sulfone is suppressed. For organic sulfides, selectivity of oxidation is especially important for detoxification of mustard gas (bis(2-chloroethyl)sulfide) or similarly toxic compounds since controlled oxidation leads to the low toxicity bis(2-chloroethyl)sulfoxide while overoxidation leads to intoxification (since bis(2-chloroethyl)sulfone presents greater toxicity to humans than the sulfide substrate). Therefore, OxP POPs capable of promoting selective oxidation of sulfides to sulfoxides have excellent potential to be used as mild and selective detoxification agents.

Oxoporphyrinogen (OxP) is a unique chromophore compound in that it is intrinsically de-aggregated allowing large quantum yields of singlet oxygen generation. Due to its structure, OxP is also an ideal building block for porous systems. In this work, we describe the first incorporation of OxP in highly stable microporous polymers strongly enhanced singlet oxygen generation for selective oxidation of organic sulfides to sulfoxides (as a model reaction) under heterogeneous conditions. The novelty of this work lies in the high stability and easy recovery of the materials, the synergetic enhancement of singlet oxygen generation in the polymers over the starting OxP, and the excellent selectivity for the oxidation reaction.

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The current clinical treatment of diabetic wounds is still based on oxygen therapy, and the slow healing of skin wounds due to hypoxia has always been a key problem in the repair of chronic skin injuries. To overcome this problem, the oxygen-producing matrix CaO2NPS based on the temperature-sensitive dihydromyricetin-loaded hydrogel was prepared. In vitro activity showed that the dihydromyricetin (DHM) oxygen-releasing temperature-sensitive hydrogel composite (DHM-OTH) not only provided a suitable oxygen environment for cells around the wound to survive but also had good biocompatibility and various biological activities. By constructing a T2D wound model, we further investigated the repairing effect of DHM-OTH on chronic diabetic skin wounds and the mechanisms involved. DHM-OTH was able to reduce inflammatory cells and collagen deposition and promote angiogenesis and cell proliferation for diabetic wound healing. These in vitro and in vivo data suggest that DHM-OTH accelerates diabetic wound repair as a novel method to efficiently deliver oxygen to wound tissue, providing a promising strategy to improve diabetic wound healing.

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Biocompatible photocatalytic water-splitting systems are promising for tissue self-oxygenation. Herein, a structure-function dual biomimetic fingerprint-like silver phosphate/polydopamine/graphitic carbon nitride (Ag3PO4/PDA/g-C3N4) heterojunction nanocomposite is proposed for enhanced solar-driven oxygen (O2) evolution in vivo in situ. Briefly, a porous nitrogen-defected g-C3N4 nanovoile (CN) is synthesized as the base. Dopamine molecules are controllably inserted into the CN interlayer, forming PDA spacers (4.28 nm) through self-polymerization-induced supramolecular-assembly. Ag3PO4 nanoparticles are then in situ deposited to create Ag3PO4/PDA/CN. The fingerprint-like structure of PDA/CN enlarges the layer spacing, thereby accelerating mass transfer and increasing reaction sites. The PDA spacer roles as excellent light harvester, electronic-ionic conductor, and redox pair through conformational changes, resulting in tailored electronic band structure, optimized carrier behavior, and reduced electrochemical impedance. In physiological conditions, Ag3PO4/PDA/CN exhibits O2 evolution rate of 45.35 µmol⋅g-1⋅h-1, 9-fold of bulk g-C3N4. The biocompatibility and in vivo oxygen supply effectiveness for biomedical applications have been verified in animal models.

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Cell growth and metabolism require an adequate supply of oxygen. However, obtaining sufficient oxygen from the blood circulating around diabetic wounds is challenging. Nevertheless, achieving a continuous and stable oxygen supply is required for these wounds to heal. Hence, in this study, we report a novel antibacterial oxygen-producing silk fibroin methacryloyl hydrogel microneedle (MN) patch comprising tips encapsulated with calcium peroxide and catalase and a base coated with antibacterial Ag nanoparticles (AgNPs). The tip of the MN patch continuously releases oxygen and inhibits the production of reactive oxygen species. This accelerates diabetic wound healing by promoting cellular accretion and migration, macrophage M2 polarization, and angiogenesis. The AgNPs at the base of the MN patch effectively combat microbial infection, further facilitating wound repair. These findings suggest that using this multifunctional oxygen-producing MN patch may be a promising strategy for diabetic wound healing in clinical settings.

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Photodynamic therapy (PDT) is a photochemical-based treatment approach that involves using light to activate photosensitizers (PSs). Attractively, PDT is one of the alternative cancer treatments due to its noninvasive technique. By utilizing the heavy atom effect, this work modified a class of formazan dyes to improve intersystem crossing (ISC) to improve reactive oxygen species (ROS) generation for PDT treatment. Two methods were used to observe the ROS generation enhanced by ISC of the synthesized complexes including, (1) recording DPBF decomposition caused by the ROS, and (2) calculating the potential energy curves for photophysical mechanisms of BF2 -formazanate dyes using the DFT and nudged elastic band (NEB) methods. The photophysical properties of the dyes were studied using spectroscopic techniques and X-ray crystallography, as well as DFT calculations. The experimental and theoretical results and in vitro cellular assays confirmed the potential use of the newly synthesized iodinated BF2 -formazanate dyes in PDT.

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The emergence of drug-resistant pathogenic microorganisms has become a public health concern, with demand for strategies to suppress their proliferation in healthcare facilities. The present study investigates the physicochemical and antimicrobial properties of carbon dots (CD-MR) derived from the methyl red azo dye. The morphological and structural analyses reveal that such carbon dots present a significant fraction of graphitic nitrogen in their structures, providing a wide emission range. Based on their low cytotoxicity against mammalian cells and tunable photoluminescence, these carbon dots are applied to bioimaging in vitro living cells. The possibility of using CD-MR to generate reactive oxygen species (ROS) is also analyzed, and a high singlet oxygen quantum efficiency is verified. Moreover, the antimicrobial activity of CD-MR is analyzed against pathogenic microorganisms Staphylococcus aureus, Candida albicans, and Cryptococcus neoformans. Kirby-Bauer susceptibility tests show that carbon dots synthesized from methyl red possess antimicrobial activity upon photoexcitation at 532 nm. The growth inhibition of C. neoformans from CD-MR photosensitization is investigated. Our results show that N-doped carbon dots synthesized from methyl red efficiently generate ROS and possess a strong antimicrobial activity against healthcare-relevant pathogens.

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The development of smart theranostic nanoplatforms has gained great interest in effective cancer treatment against the complex tumor microenvironment (TME), including weak acidity, hypoxia, and glutathione (GSH) overexpression. Herein, a TME-responsive nanoplatform named PMICApt /ICG, based on PB:Mn&Ir@CaCO3 Aptamer /ICG, is designed for the competent synergistic photothermal therapy and photodynamic therapy (PDT) under the guidance of photothermal and magnetic resonance imaging. The nanoplatform's aptamer modification targeting the transferrin receptor and the epithelial cell adhesion molecule on breast cancer cells, and the acid degradable CaCO3 shell allow for effective tumor accumulation and TME-responsive payload release in situ. The nanoplatform also exhibits excellent PDT properties due to its ability to generate O2 and consume antioxidant GSH in tumors. Additionally, the synergistic therapy is achieved by a single wavelength of near-infrared laser. RNA sequencing is performed to identify differentially expressed genes, which show that the expressions of proliferation and migration-associated genes are inhibited, while the apoptosis and immune response gene expressions are upregulated after the synergistic treatments. This multifunctional nanoplatform that responds to the TME to realize the on-demand payload release and enhance PDT induced by TME modulation holds great promise for clinical applications in tumor therapy.

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Rheumatoid arthritis (RA) is a chronic autoimmune disease commonly associated with the accumulation of hyperactive immune cells (HICs), particularly macrophages of pro-inflammatory (M1) phenotype, accompanied by the elevated level of reactive oxygen species (ROS), decreased pH and O2 content in joint synovium. In this work, an immunomodulatory nanosystem (IMN) is developed for RA therapy by modulating and restoring the function of HICs in inflamed tissues. Manganese tetraoxide nanoparticles (Mn3 O4 ) nanoparticles anchored on UiO-66-NH2 are designed, and then the hybrid is coated with Mn-EGCG film, further wrapped with HA to obtain the final nanocomposite of UiO-66-NH2 @Mn3 O4 /Mn-EGCG@HA (termed as UMnEH). When UMnEH diffuses to the inflammatory site of RA synovium, the stimulation of microwave (MW) irradiation and low pH trigger the slow dissociation of Mn-EGCG film. Then the endogenously overexpressed hydrogen peroxide (H2 O2 ) disintegrates the exposed Mn3 O4 NPs to promote ROS scavenging and O2 generation. Assisted by MW irradiation, the elevated O2 content in the RA microenvironment down-regulates the expression of hypoxia-inducible factor-1α (HIF-1α). Coupled with the clearance of ROS, it promotes the re-polarization of M1 phenotype macrophages into anti-inflammatory (M2) phenotype macrophages. Therefore, the multifunctional UMnEH nanoplatform, as the IMN, exhibits a promising potential to modulate and restore the function of HICs and has an exciting prospect in the treatment of RA.

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Construction of metal-organic cages with unique architecture and guest binding abilities is highly desirable. Herein, we report the synthesis of a distorted trigonal cage (1) from a twisted tetratopic ligand (L) and a PdII acceptor. Surprisingly, 1 exhibited a complete structural reorganization of its building units in the presence of C70 and C60 to form guest-encapsulated tetragonal cages, (C70 )2 @2 and (C60 )2 @2, respectively. These guest-bound cages were found to be potential 1 O2 generators, with the former effectively catalyzing two different varieties of 1 O2 -mediated oxidation reactions.

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Large bone defects resulting from fractures and disease are a major clinical challenge, being often unable to heal spontaneously by the body's repair mechanisms. Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration. However, replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells. Therefore, reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair. Herein, we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels (CPP-L/GelMA) as a "bone microenvironment regulative hydrogel" to reverse the hypoxic microenvironment in bone defects region. CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase (CAT) and ROS-responsive oxygen-releasing nanoparticles (PFC@PLGA/PPS) co-loaded liposome (CCP-L) and GelMA hydrogels. Under hypoxic condition, CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks. The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis. Finally, CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway. Hence, CPP-L/GelMA, as a bone microenvironment regulative hydrogel for bone tissue respiration, can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region, possessing of great clinical therapeutic potential.

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Increasing O2 demand and excessive ROS production are the main features of arthritic microenvironment in rheumatoid arthritis (RA) joints and further play pivotal roles in inflammation exacerbation. In this work, a system of in situ regulation of arthritic microenvironment based on nanomotor strategy is proposed for active RA therapy. The synthesized MnO2 -motors enable catalytic regulation of RA microenvironment by consuming the overproduced H2 O2 and generating O2 synergistically. The generated O2 under H2 O2 -rich conditions functions as inflammation detector, propellant for enhanced diffusion, as well as ameliorator for the hypoxic synovial microenvironment. Owing to O2 generation and inflammation scavenging, the MnO2 -motors block the re-polarization of pro-inflammatory macrophages, which results in significantly decreased secretion of multiple pro-inflammatory cytokines both in vitro and in vivo. In addition, intra-articular administration of MnO2 -motors to collagen-induced arthritis rats (CIA rats) effectively alleviates hypoxia, synovial inflammation, bone erosion, and cartilage degradation in joints. Therefore, the proposed arthritic regulation strategy shows great potential to seamlessly integrate basic research of RA with clinical translation.

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