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The assembly of pH-responsive DNA-based, phase-separated microdroplets (MDs) coacervates, consisting of frameworks composed of Y-shaped nucleic acid modules crosslinked by pH-responsive strands, is introduced. The phase-separated MDs reveal dynamic pH-stimulated switchable or oscillatory transient depletion and reformation. In one system, a photoisomerizable merocyanine/spiropyran photoacid is used for the light-induced pH switchable modulation of the reaction medium between the values pH=6.0-4.4. The dynamic transient photochemically-induced switchable depletion/reformation of phase-separated MDs, follows the rhythm of pH changes in solution. In a second system, the Landolt oscillatory reaction mixture pH 7.5→4.2→7.5 is applied to stimulate the oscillatory depletion/reformation of the MDs. The autonomous dynamic oscillation of the assembly/disassembly of the MDs follows the oscillating pH rhythm of the reaction medium., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, we report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C-H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner., (© 2024 Wiley-VCH GmbH.)

Phthalocyanines are versatile photodynamic therapy agents whose biological activity depends on their aggregation state, which is expected to be influenced by binding to biomolecules. Here, guanine-rich nucleic acid binding of a water-soluble cationic, regiopure C 4h zinc phthalocyanine bearing four triethylene glycol methyl ether and four N-methyl-4-pyridinium substituents (1) is reported. In contrast to double-stranded DNA, guanine systems GpG, (GG) 10 , poly(G) and quadruplex DNA are shown to effectively disrupt phthalocyanine aggregates in buffered solution. This process is accompanied by evolution of the Q-band absorbance and enhanced emission. Increasing the sequence length from GpG to (GG) 10 increases the binding and confirms the importance of multiple binding interactions. Enhanced binding in the presence of KCl suggests the importance of nucleobase hydrogen-bonded mosaics in phthalocyanine binding. Notably, the (GT) 10 sequence is even more effective than quadruplex and pure guanine systems at disrupting the aggregates of 1. Significant time-dependent binding of 1 with poly(G) reveals biexponential binding over minutes and hours, which is linked to local conformations of poly(G) that accommodate monomers of 1 over time. The study highlights the ability of biomacromolecules to disrupt phthalocyanines aggregates over time, which is an important consideration when rationalizing photoactivity of photosensitizers in-vivo., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-h compound exposure) assay developed within our laboratories. The IC 50 values of the active compounds were determined using the rapid assay and six compounds displayed an IC 50 value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC 50 value <5 μM against one or more pancreatic cancer cell lines., (© 2024 Wiley-VCH GmbH.)

Melanoma has emerged as a significant threat to human life and health. Microneedle (MN)-mediated transdermal drug delivery (TDD) has garnered attention in melanoma treatment for bypassing the first-pass effect. However, the propensity of melanoma to metastasize presents substantial challenges for MN mediated local treatment. Developing systemic therapies, such as immunotherapy in combination with TDD, is crucial for achieving effective melanoma treatment. Herein, a polyvinyl alcohol (PVA) MN-mediated multifunctional TDD system, designated MN@PDA@1-MT/CUR/DOX@HA (MN@PMCDH), was developed for synergetic chemotherapy/photothermal/immunotherapy of melanoma. PMCDH nanomedicines penetrate deep skin layers through MNs, accumulate at tumor sites guided by hyaluronic acid (HA), and selectively release drugs in response to the acidic tumor microenvironment and near-infrared (NIR) stimulation. Released curcumin (CUR) significantly enhances the efficacy of photothermal therapy (PTT) and chemotherapy, as well as improves the induction of immunogenic cell death (ICD) by increasing melanoma sensitivity to polydopamine (PDA)-mediated photothermal effects and doxorubicin (DOX). Moreover, the incorporation of 1-methyltryptophan (1-MT) to reverse the tumor immunosuppressive microenvironment can further enhance the effects of immunotherapy. In vitro studies revealed that the MN@PMCDH system can effectively induce ICD and inhibit tumor cell growth. Additionally, remarkable deep tumor cell inhibition effects are also achieved in 3D tumor models., (© 2024 Wiley-VCH GmbH.)

Anisotropic polydopamine nanobowls (PDA NBs) show significant promise in biomedicine, distinguished by their unique optical properties and superior cellular uptake compared to spherical nanoparticles. This study presents a novel approach for creating multistimuli-activated PDA NB-armored emulsions, encapsulating perfluorohexane (NB-H) and perfluoropentane (NB-P) cores, with applications in controlled delivery and ultrasound imaging. Thermal and photothermal activation induced distinct responses in the emulsions, as evidenced by optical microscopy and thermogravimetric analysis. For the first time, neutron scattering techniques (SANS and USANS) under contrast matching conditions are applied to investigate these materials, revealing detailed droplet and microbubble structures and phase transition dynamics. These results show that NB-H droplets resist phase change under direct heating, whereas NB-P droplets respond more readily, exhibiting significant bubble formation. During photothermal activation with short near-infrared (NIR) exposure (15 min at 400 mW cm -2 ), SANS and USANS analyses reveal varying degrees of phase transition, proving this activation method to be more effective than direct heating. Importantly, NB-H and NB-P droplets have excellent ultrasound contrast enhancement and biocompatibility, indicating their potential for contrast-enhanced ultrasound imaging, theranostics, and photothermal applications. This comprehensive study advances the understanding of multifunctional colloidal materials in biomedicine, contributing essential knowledge to this rapidly evolving field., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

In the era of "Great Health", maintaining an appropriate level of vitamin C is crucial for human health as it directly impacts the proper functioning of the immune system. In this study, a handheld nonenzymatic electrochemical sensor based on biomimetic material prussian blue functionalized polydopamine is proposed for point-of-care testing (POCT) of vitamin C in human fluids. Particularly, Prussian blue, known as a bio-antidote, and polydopamine, a main component of cuttlefish ink, ensure the safety and reliability of home testing. The experimental results quantitatively demonstrate that this electrochemical POCT sensor enables rapid and accurate determination of vitamin C with a wide linear detection range from 0.2 to 200 µm, a low limit of detection at 0.03 µm, and high sensitivity at 0.33 µA µm -1  cm -2 . More importantly, the performance evaluation using human urine and saliva samples confirms satisfactory accuracy and recovery rates for vitamin C determination by this electrochemical POCT sensor. Thus, the proposed handheld electrochemical POCT sensor holds potential utility as an affordable tool for VC determination and home-based healthcare., (© 2024 Wiley‐VCH GmbH.)

Nitroxide-mediated polymerization (NMP) and nitroxide exchange reaction (NER) are very efficient methodologies that require only suitable alkoxyamine derivatives and create different polymeric architectures in a controlled manner. Herein, the synthesis of star polymers containing TEMPO-substituted symmetric zinc phthalocyanine (ZnPc) is presented via NMP and NER. Moreover, linear polymer formation is conducted in a single arm on TEMPO-substituted asymmetric ZnPc to elucidate the properties of star polymers. All linear and star polymers are characterized by FT-IR, UV-vis, fluorescence, GPC, NMR, and EPR techniques. The results show that the proposed reactions are capable of forming controlled star-shaped polymers. The increasing arm number (from a single to four arms) results in variable dispersity values (Đ) (1.2-3) due to different arm lengths, especially in NMP. However, this difficulty has been overcome via NER, and star polymers have been successfully synthesized with relatively low molecular weight (30 K > 10 K) and low dispersity (1.2-1.9). The results clearly indicate that while styrene and 4-vinyl benzyl chloride monomers are introduced to the structure equally, star polymers with phthalocyanine can be synthesized in a controlled manner, and their quarternized derivatives have the potential to be effective as photoactive agents in photodynamic therapy., (© 2024 The Author(s). Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

Phthalocyanines (Pcs) are widely developed in cancer phototherapy due to their definite chemical structure and tunable photosensitivity. However, their in vivo application is hampered by low water solubility and non-specific biodistribution. Here,a strategy of sialylation-modulation is developed for the first time to highly improve the bioavailability of Pcs. The sialylated Pcs (ZnPc-4SA) not only has good hydrophilicity, but also can self-assemble into nanoparticles (ZnPc-4SA NPs). These nanoformulations retain the excellent photophysical properties of Pcs, which in turn reflects excellent optoacoustic and phototherapeutic properties. Importantly, ZnPc-4SA NPs exhibit boosted tumor accumulation due to the passive targeting and sialic acid-mediated E-selectin targeting. Besides, the phototoxicity of ZnPc-4SA NPs can effectively trigger cell apoptosis and tumor elimination upon laser irradiation. Therefore, sialylation engineering strategy provides a new option for hydrophobic drugs modification with enhanced tumor theranostics., (© 2024 Wiley‐VCH GmbH.)

Depleted uranium (DU), when accidentally released from the nuclear industry, can enter the human body and cause kidney damage, as DU induces oxidative damage and apoptosis through mitochondrial pathways and inflammatory reactions. The existing nanoparticles used to treat DU injury have low bioavailability and poor targeting. In this study, mesoporous polydopamine (MPDA), poly-(ethylene glycol) (PEG), and triphenylphosphonium (TPP) are combined to develop a novel mitochondrion-targeting bifunctional nanoparticle, MPDA-PEG-TPP, and confirm that it can protect the kidneys from DU. This study demonstrates the high selectivity of MPDA-PEG-TPP for uranyl in uranyl chelate assays and its promising efficiency in uranyl sequestration from the kidneys, lungs, and femurs, following immediate or delayed administration of MPDA-PEG-TPP nanoparticles. In vitro assays confirm its efficiency in removing reactive oxygen species and targeting the mitochondria. In addition, in vitro and in vivo assays confirm that MPDA-PEG-TPP can reduce mitochondrial dysfunction and ameliorate kidney injury. These results suggest that MPDA-PEG-TPP is a valuable agent for ameliorating the DU-induced kidney injury., (© 2024 Wiley‐VCH GmbH.)

As the misuse of antibiotics increases bacterial resistance, the treatment of infected wounds caused by bacteria encounters significant challenges. Conventional antimicrobial dressings often fall short in their ability to inhibit bacterial infections while simultaneously promoting wound healing. To address this issue, a polysaccharide self-healing hydrogel (CPP@PDA/Que3) wound dressing is successfully developed by incorporating quercetin and polydopamine nanoparticles into a carboxymethyl chitosan matrix. The dressing can be easily injected locally to create a protective barrier over the wound, effectively stopping bleeding and rapidly inhibiting inflammation. Furthermore, the CPP@PDA/Que3 hydrogel exhibits remarkable antioxidant and antibacterial properties, stemming from the combination of quercetin and near-infrared (NIR) photothermal therapy. It demonstrates the ability to eliminate 99.52% of Staphylococcus aureus and 99.39% of Escherichia coli in in vitro antibacterial experiments. Additionally, the in vivo wound healing experiment shows a healing rate of ≈97%. The experimental results indicate that under NIR laser (808 nm) irradiation, the polysaccharide-based hydrogel dressing significantly inhibits bacterial growth, reduces oxidative stress, expedites angiogenesis, and thereby accelerates the transition from inflammation to wound healing. In summary, the CPP@PDA/Que3 hydrogel exhibits significant potential as a wound dressing, providing a novel approach for clinically advancing the treatment of bacterial wounds., (© 2024 Wiley‐VCH GmbH.)

Uncontrolled hemorrhage, especially in non-compressible and deep wounds, remains a critical issue in emergency and surgical care. Existing hemostatic powders often lack rapid gelation, mechanical robustness, and adequate adherence, increasing the risk of rebleeding under high-pressure blood flow. To address these limitations, PQPP, a novel self-gelling hemostatic material composed of polyacrylamide/quaternized chitosan coacervates and polydopamine nanoparticles is developed. PQPP can rapidly absorb blood within 2 s, undergoes in situ gelation, and forms a robust adhesive hydrogel to effectively seal wounds. Its efficacy stems from the electrostatic adsorption and catechol functional groups of polydopamine nanoparticles. Importantly, PQPP exhibits high burst pressure resistance, excellent blood cell aggregation capability, outstanding biocompatibility, and antibacterial properties. Comprehensive in vitro and in vivo studies, including cytotoxicity and blood compatibility tests, as well as trials in mouse liver, heart, and vascular injury models, demonstrate PQPP's superior hemostatic performance under high-pressure conditions without causing inflammation. With its rapid gelation, robust adhesion, and mechanical integrity, PQPP represents a promising hemostatic material for immediate wound management in surgical and emergency applications., (© 2024 Wiley‐VCH GmbH.)

The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can "warm" the "cold" tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr 3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

As a promising approach for breast cancer treatment, photothermal therapy (PTT) features high spatial selectivity, noninvasiveness, and minimal drug resistance. IR780 (a near-infrared fluorescent dye) serves as an effective photosensitizer in PTT cancer therapy. However, the clinical application of IR780 in PTT has been hindered by its poor water solubility and unstable photostability. In this study, a genetically engineered dual-functional fusion protein tLyP-1-MGF6 is successfully constructed and expressed, which presents a novel use of hydrophobin MGF6 for its amphiphilicity combined with the tumor-penetrating peptide tLyP-1 to create an innovative carrier for IR780. These results show this fusion protein serving as a biodegradable and biocompatible carrier, significantly improves the water solubility of IR780 when formulated into nanoparticles. These studies demonstrate that the IR780@tLyP-1-MGF6 nanoparticles significantly enhance tumor targeting and photothermal therapeutic efficacy in comparison with control in vitro and in vivo. These advancements highlight the potential of the unique combination hydrophobin-based IR780 delivery system as a multifunctional nanoplatform for integrated imaging and targeted photothermal treatment of breast cancer., (© 2024 Wiley‐VCH GmbH.)

Herein, we report design, synthesis and characterization of a new library of 7-azaindole N-ethyl linked 1,2,3-triazoles containing ethylene as a spacer unit, and evaluation of all the synthesized compounds for their antimicrobial properties. Antibacterial potential was checked against two Gram positive (B. subtilis and S. aureus) and two Gram negative (E. coli and P. aeruginosa) bacterial strains while antifungal potential was assayed against two fungal strains (C. albicans and A. niger). All the tested compounds showed satisfactory antibacterial potency in comparison to reference drug ciprofloxacin with MIC values ranging from 0.0108 to 0.0432 μmol/mL. Interestingly, except two, all the target compounds showed better antifungal property as compared to the reference drug fluconazole with MIC values less than 0.0408 μmol/mL. One of the compounds exhibited two-fold better antifungal potential in comparison to fluconazole. Furthermore, in-silico ADMET and DFT studies reported drug likeness behavior and chemical reactivity parameters, respectively. The cytotoxicity results on substrate azide 3 and most potent 1,2,3-triazoles (5 d and 5 l) were found to be non-toxic., (© 2024 Wiley-VCH GmbH.)

Interest in antibacterial nanomaterials has surged in recent years, driven by the rise in antibiotic resistance among microbes. However, their practical application remains limited because many crucial properties have yet to be thoroughly investigated. In this study, we have developed novel nanofibrous membranes based on hydrophilic polyacrylonitrile (PAN) or hydrophobic polycaprolactone (PCL) with embedded hydrophilic or hydrophobic zinc(II)phthalocyanines (ZnPcs) as photosensitizers and investigated their water disinfection properties. Several key characteristics were evaluated to link the activity of the material and composition/structure. As demonstrated by reflectance UV/Vis spectroscopy, the aggregation states of dyes within the polymer support vary significantly. We have proposed and validated the use of fluorescence lifetime imaging (FLIM) for visualizing "active sites" in the membranes. The results of this study provide useful insights for the engineering of photoactive nanomaterials with tailor-made properties and highlight the crucial role of the nature of polymeric support in modulating the material's activity., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Heme enzymes play a central role in a medley of reactivities within a wide variety of crucial biological systems. Their active sites are highly decorated with pivotal evolutionarily optimized non-covalent interactions that precisely choreograph their biological functionalities with specific regio-, stereo-, and chemo-selectivities. Gaining a clear comprehension of how such weak interactions within the active sites control reactivity offers powerful information to be implemented into the design of future therapeutic agents that target these heme enzymes. To shed light on such critical details pertaining to tryptophan dioxygenating heme enzymes, this study investigates the indole dioxygenation reactivities of Lewis acid-activated heme superoxo model systems, wherein an unprecedented kinetic behavior is revealed. In that, the activated heme superoxo adduct is observed to undergo indole dioxygenation with the intermediacy of a non-covalently organized precursor complex, which forms prior to the rate-limiting step of the overall reaction landscape. Spectroscopic and theoretical characterization of this precursor complex draws close parallels to the ternary complex of heme dioxygenases, which has been postulated to be of crucial importance for successful 2,3-dioxygenative cleavage of indole moieties., (© 2024 Wiley-VCH GmbH.)

Bifunctional catalase-peroxidase (KatG) features a posttranslational methionine-tyrosine-tryptophan (MYW) crosslinked cofactor crucial for its catalase function, enabling pathogens to neutralize hydrogen peroxide during infection. We discovered the presence of indole nitrogen-linked hydroperoxyl adduct (MYW-OOH) in Mycobacterium tuberculosis KatG in the solution state under ambient conditions, suggesting its natural occurrence. By isolating predominantly MYW-OOH-containing KatG protein, we investigated the chemical stability and functional impact of MYW-OOH. We discovered that MYW-OOH inhibits catalase activity, presenting a unique temporary lock. Exposure to peroxide or increased temperature removes the hydroperoxyl adduct from the protein cofactor, converting MYW-OOH to MYW and restoring the detoxifying ability of the enzyme against hydrogen peroxide. Thus, the N-linked hydroperoxyl group is releasable. KatG with MYW-OOH represents a catalase dormant, but primed, state of the enzyme. These findings provide insight into chemical strategies targeting the bifunctional enzyme KatG in pathogens, highlighting the role of N-linked hydroperoxyl modifications in enzymatic function., (© 2024 Wiley-VCH GmbH.)

A self-assemble amphiphilic diblock copolymer that can incorporate iron oxide nanocubes (IONCs) in chain-like assemblies as heat mediators for magnetic hyperthermia (MHT) and tuneable amounts of IR780 dye as agent for photothermal therapy (PTT) is developed. MHT-heating performance of photobeads in viscous media have the same heat performances in water at magnetic field conditions of clinical use. Thanks to IR780, the photobeads are activated by infrared laser light within the first biological window (808 nm) with a significant enhancement of photo-stability of IR780 enabling the raise of the temperature at therapeutic values during multiple PTT cycles and showing unchanged optical features up to 8 days. Moreover, the photobeads fluorescent signal is preserved once internalized by glioblastoma multiforme (GBM) cells. Peculiarly, the photobeads are used as toxic agents to eradicate thermo-resistant GBM cells at mild heat, as low as 41 °C, with MHT and PTT both of clinical use. Indeed, a high U87 GBM cell mortality percentage is obtained only with dual MHT/PTT while each single treatment dose not provide the same cytotoxic effects. Only for the combined treatment, the cell death mechanism is assigned to clear sign of apoptosis as observed by structural/morphological cell studies and enhanced lysosome permeability., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Parkinson's disease (PD) pathology speculates that neuromelanin (NM) and iron ions play a significant role in physiological and pathological conditions of PD. Because the difficult accessibility of NM has limited targeted research, synthetic melanin-like nanoparticles have been used to instead. In this report, the eumelanin and pheomelanin-like polydopamine (PDA) nanoparticles are prepared that can be used to simulate natural NM with or without chelating iron ion and studied the redox effects in vitro and in vivo on neuronal cells and PD. The synthetic pheomelanin-like PDA nanoparticles have much stronger redox activity than eumelanin-like PDA nanoparticles without or with iron ion. They can protect neurons by scavenging reactive oxygen species (ROS), while cause neuronal cell death and PD due to excessive binding of iron ions. This work provides new evidence for the relationship among two structural components of NM and iron in PD as well as displays the different effects on the roles of eumelanin and pheomelanin in redox activity under physiological or pathological conditions, which provide a new effective choice for cellular and animal models of PD and offer theoretical guidance for targeted treatment and mechanism research on PD., (© 2024 Wiley‐VCH GmbH.)

Bacterial biofilm formation is closely associated with persistent infections of medical implants, which can lead to implantation failure. Additionally, the reconstruction of the vascular network is crucial for achieving efficient osseointegration. Herein, an anti-biofilm nanoplatform based on L-arginine (LA)/new indocyanine green (NICG) that is anchored to strontim titanium oxide (SrTiO 3 ) nano-arrays on a titanium (Ti) substrate by introducing polydopamine (PDA) serving as the interlayer is designed and successfully fabricated. Near-infrared light (NIR) is used to excite NICG, generating reactive oxygen species (ROS) that react with LA to release nitric oxide (NO) molecules. Utilizing the concentration-dependent effect of NO, high power density NIR irradiation applied during the early stage after implantation to release a high concentration of NO, which synergized with the photothermal effect of PDA to eliminate bacterial biofilm. Subsequently, the irradiation power density can be finely down-regulated to reduce the NO concentration in subsequent treatment for accelerating the reconstruction of blood vessels. Meanwhile, SrTiO 3 nano-arrays improve the hydrophilicity of the implant surface and slowly release strontium (Sr) ions for continuously optimizing the osteogenic microenvironment. Effective biofilm elimination and revascularization alongside the continuous optimization of the osteogenic microenvironment can significantly enhance the osseointegration of the functionalized Ti implant in in vivo animal experiments., (© 2024 Wiley‐VCH GmbH.)

Biological effectors play critical roles in augmenting the repair of cartilage injuries, but it remains a challenge to control their release in a programmable, stepwise fashion. Herein, a hybrid system consisting of polydopamine (PDA) nanobottles embedded in a hydrogel matrix to manage the release of biological effectors for use in cartilage repair is reported. Specifically, a homing effector is load in the hydrogel matrix, together with the encapsulation of a cartilage effector in PDA nanobottles filled with phase-change material. In action, the homing effector is quickly released from the hydrogel in the initial step to recruit stem cells from the surroundings. Owing to the antioxidation effect of PDA, the recruited cells are shielded from reactive oxygen species. The cartilage effector is then slowly released from the nanobottles to promote chondrogenic differentiation, facilitating cartilage repair. Altogether, this strategy encompassing recruitment, protection, and differentiation of stem cells offers a viable route to tissue repair or regeneration through stem cell therapy., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Tumor microenvironment, characterized by dense extracellular matrix and severe hypoxia, has caused pronounced resistance to photodynamic therapy (PDT). Herein, it has designed an artificial nitric oxide (NO) nanotractor with a unique "motor-cargo" structure, where a photoswitching upconversion nanoparticle (UCNP) core serves as the optical engine to harvest NIR light and asymmetrically coated mesoporous silica (SiO 2 ) shell acts as a cargo unit to load nitric oxide (NO) fuel molecule (RBS, Roussin's black salt) and PDT photosensitizer (ZnPc, zinc phthalocyanine). Upon illumination by 980 nm light, the UCNP emits blue light to excite RBS salt and release NO gas. On one hand, NO is used as the driving force to propel the particle with a high speed of ≈194 µm s -1 that generates significant rupture stress (over 0.95 kPa) on cell membrane to promote cellular endocytosis and intratumoral penetration. On the other hand, NO enables to alleviate tumor hypoxia by inhibiting cellular respiration as an oxygen conserver. When the excitation is subsequently switched to 808 nm light, the UCNP emits red light, triggering ZnPc to produce large amount of reactive oxygen species for PDT treatment. This study explores Janus-typed nanostructures for cell-particle interaction and gas-assisted phototherapy, opening avenues for versatile bioapplications., (© 2024 Wiley‐VCH GmbH.)

Ferroptosis nano-inducers have drawn considerable attention in the treatment of malignant tumors. However, low intratumoral hydrogen peroxide level and complex biological barriers hinder the ability of nanomedicines to generate sufficient reactive oxygen species (ROS) and achieve tumor penetration. Here a near-infrared (NIR)-driven ROS self-supplying nanomotor is successfully designed for synergistic tumor chemodynamic therapy (CDT) and photothermal therapy (PTT). Janus nanomotor is created by the asymmetrical modification of polydopamine (PDA) with zinc peroxide (ZnO 2 ) and subsequent ferrous ion (Fe 2+ ) chelation via the polyphenol groups from the PDA, here refer as ZnO 2 @PDA-Fe (Z@P-F). ZnO 2 is capable of slowly releasing hydrogen peroxide (H 2 O 2 ) into an acidic tumor microenvironment (TME) providing sufficient ingredients for the Fenton reaction necessary for ferroptosis. Upon NIR laser irradiation, the loaded Fe 2+ is released and a thermal gradient is simultaneously formed owing to the asymmetric PDA coating, thus endowing the nanomotor with self-thermophoresis based enhanced diffusion for subsequent lysosomal escape and tumor penetration. Therefore, the release of ferrous ions (Fe 2+ ), self-supplied H 2 O 2 , and self-thermophoresis of nanomotors with NIR actuation further improve the synergistic CDT/PTT efficacy, showing great potential for active tumor therapy., (© 2024 Wiley‐VCH GmbH.)

The repair and reconstruction of large-scale bone defects face enormous challenges because of the failure to reconstruct the osteo-vascularization network. Herein, a near-infrared (NIR) light-responsive hydrogel system is reported to achieve programmed tissue repair and regeneration through the synergetic effects of on-demand drug delivery and mild heat stimulation. The spatiotemporal hydrogel system (HG/MPa) composed of polydopamine-coated Ti 3 C 2 T x MXene (MP) nanosheets decorated with acidic fibroblast growth factor (aFGF, a potent angiogenic drug) and hydroxypropyl chitosan/gelatin (HG) hydrogel is developed to orchestrate the reconstruction of the osteo-vascularization network and boost bone regeneration. Upon exposure to NIR light irradiation, the engineered HG/MPa hydrogel can achieve the initial complete release of aFGF to induce rapid angiogenesis and provide sufficient blood supply, maximizing its biofunction in the defect area. This integrated hydrogel system demonstrated good therapeutic efficacy in promoting cell adhesion, proliferation, migration, angiogenesis, and osteogenic differentiation through periodic NIR irradiation. In vivo, animal experiments further revealed that the spatiotemporalized hydrogel platform synergized with mild photothermal treatment significantly accelerated critical-sized bone defect healing by increasing the osteo-vascularization network density, recruiting endogenous stem cells, and facilitating the production of osteogenesis/angiogenesis-related factors. Overall, smart-responsive hydrogel could enhance the reconstruction of the osteo-vascularization network in bone regeneration., (© 2024 Wiley‐VCH GmbH.)

Large segmental bone defects often lead to nonunion and dysfunction, posing a significant challenge for clinicians. Inspired by the intrinsic bone defect repair logic of "vascularization and then osteogenesis", this study originally reports a smart implantable hydrogel (PDS-DC) with high mechanical properties, controllable scaffold degradation, and timing drug release that can proactively match different bone healing cycles to efficiently promote bone regeneration. The main scaffold of PDS-DC consists of polyacrylamide, polydopamine, and silk fibroin, which endows it with superior interfacial adhesion, structural toughness, and mechanical stiffness. In particular, the adjustment of scaffold cross-linking agent mixing ratio can effectively regulate the in vivo degradation rate of PDS-DC and intelligently satisfy the requirements of different bone defect healing cycles. Ultimately, PDS hydrogel loaded with free desferrioxamine (DFO) and CaCO 3 mineralized ZIF-90 loaded bone morphogenetic protein-2 (BMP-2) to stimulate efficient angiogenesis and osteogenesis. Notably, DFO is released rapidly by free diffusion, whereas BMP-2 is released slowly by pH-dependent layer-by-layer disintegration, resulting in a significant difference in release time, thus matching the intrinsic logic of bone defect repair. In vivo and in vitro results confirm that PDS-DC can effectively realize high-quality bone generation and intelligently regulate to adapt to different demands of bone defects., (© 2024 Wiley‐VCH GmbH.)

Isodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional-group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five-membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology., (© 2024 Wiley-VCH GmbH.)

Photodynamic therapy (PDT) is a clinical modality based on the irradiation of different diseases, mostly tumours, with light following the selective uptake of a photosensitiser by the pathological tissue. In this study, two new silicon(IV)phtalocyanines (SiPcs) functionalized at both axial positions with a PSMA inhibitor are reported as candidate photosensitizers for PDT of prostate cancer, namely compounds SiPc-PQ(PSMAi) 2 and SiPc-OSi(PSMAi) 2 . These compounds share the same PSMA-binding motif, but differ in the linker that connects the inhibitor moiety to the Si(IV) atom: an alkoxy (Si-O-C) bond for SiPc-PQ(PSMAi) 2 , and a silyloxy (Si-O-Si) bond for SiPc-OSi(PSMAi) 2 . Both compounds were synthesized by a facile synthetic route and fully characterized by 2D NMR, mass spectrometry and absorption/fluorescence spectrophotometry. The PDT agents showed a suitable solubility in water, where they essentially exist in monomeric form. SiPc-PQ(PSMAi) 2 showed a higher singlet oxygen quantum yield Φ Δ , higher fluorescence quantum yields Φ F and better photostability than SiPc-OSi(PSMAi) 2 . Both compounds were efficiently taken up by PSMA(+) PC3-PIP cells, but not by PSMA(-) PC3-FLU cells. However, SiPc-PQ(PSMAi) 2 showed a more specific photoinduced cytotoxicity in vitro, which is likely attributable to a better stability of its water solutions., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)

Near-infrared photosensitizers are valuable tools to improve treatment depth in photodynamic therapy (PDT). However, their low singlet oxygen ( 1 O 2 ) generation ability, indicated by low 1 O 2 quantum yield, presents a formidable challenge for PDT. To overcome this challenge, the heptamethine cyanine was decorated with biocompatible S (Scy7) and Se (Secy7) atom. We observe that Secy7 exhibits a redshift in the main absorption to ~840 nm and an ultra-efficient 1 O 2 generation capacity. The emergence of a strong intramolecular charge transfer effect between the Se atom and polymethine chain considerably narrows the energy gap (0.51 eV), and the heavy atom effect of Se strengthens spin-orbit coupling (1.44 cm -1 ), both of which greatly improved the high triplet state yield (61 %), a state that determines the energy transfer to O 2 . Therefore, Secy7 demonstrated excellent 1 O 2 generation capacity, which is ~24.5-fold that of indocyanine green, ~8.2-fold that of IR780, and ~1.3-fold that of methylene blue under low-power-density 850 nm irradiation (5 mW cm -2 ). Secy7 exhibits considerable phototoxicity toward cancer cells buried under 12 mm of tissue. Nanoparticles formed by encapsulating Secy7 within amphiphilic polymers and lecithin, demonstrated promising antitumor and anti-pulmonary metastatic effects, exhibiting remarkable potential for advancing PDT in deep tissues., (© 2024 Wiley-VCH GmbH.)

The emergence of drug resistance in cancer cells eventually causing relapse is a serious threat that demands new advances. Upregulation of the ATP-dependent binding cassette (ABC) transporters, such as ABCB1, significantly contributes to the emergence of drug resistance in cancer. Despite more than 30 years of therapeutic discovery, and several generations of inhibitors against P-gp, the search for effective agents that minimize toxicity to human cells, while maintaining efflux pump inhibition is still underway. Leads derived from natural product scaffolds are well-known to be effective in various therapeutic approaches. Inspired by the biosynthetic pathway to Nocardioazine A, a marine alkaloid known to inhibit the P-gp efflux pump in cancer cells, we devised a regioselective pathway to create structurally unique indole-C3-benzyl cyclo-L-Trp-L-Trp diketopiperazines (DKPs). Using bat cells as a model to derive effective ABCB1 inhibitors for targeting human P-gp efflux pumps, we have recently identified exo-C3-N-Dbn-Trp2 (13) as a lead ABCB1 inhibitor. This C3-benzylated lead inhibited ABCB1 better than Verapamil. [21] Additionally, C3-N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells and had no adverse effect on cell proliferation in cell cultures. For a clearer structure-activity relationship, we developed a broader screen to test C3-functionalized pyrroloindolines as ABCB1 inhibitors and observed that C3-benzylation is outperforming respective isoprenylated derivatives. Results arising from the molecular docking studies indicate that the interactions at the access tunnel between ABCB1 and the inhibitor result in a powerful predictor for the efficacy of the inhibitor. Based on fluorescence-based assays, we conclude that the most efficacious inhibitor is the p-cyano-derived exo-C3-N-Dbn-Trp2 (33 a), closely followed by the p-nitro substituted analogue. By combining assay results with molecular docking studies, we further correlate that the predictions based on the inhibitor interactions at the access tunnel provide clues about the design of improved ABCB1 inhibitors. As it has been well documented that ABCB1 itself is powerfully engaged in multi-drug resistance, this work lays the foundation for the design of a new class of inhibitors based on the endogenous amino acid-derived cyclo-L-Trp-L-Trp DKP scaffold., (© 2024 Wiley-VCH GmbH.)

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., (© 2024 Wiley-VCH GmbH.)

Self-assembly has proven to be one of the effective methods for the formation of nanoscale therapeutics without the need to use nanodelivery systems. Such minimal models of supramolecular systems formed from amphiphilic photosensitizers (PS) have recently emerged as a new class of photoactive systems, providing unique and in some cases superior activities. Although the mechanism of photogenerated reactive oxygen species (ROS) in such systems is studied and to a certain extent understood, there are very limited studies investigating the influence of intricate environmental factors, including those occurring in the cellular environment, on the self-assembly and thus the activity of the system. Understanding the optimal conditions for the formation of active PS aggregates is an important area of research in the field of photodynamic therapy (PDT), as it is directly linked to the optimal treatment dose. In this study, we describe the synthesis, self-assembly properties, photophysical characterization, and photobiological efficacy of structurally closely related low-symmetry phthalocyanine derivatives. Studying the decay behavior of the PS fluorescence lifetime in the presence of molecular crowders and different bacterial strains, we found that certain derivatives exhibited adaptive behavior and change in activity, while others demonstrated non-adaptive characteristics., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Meticulously engineered nanomaterials achieve significant advances in the diagnosis and therapy of solid tumors by improving tumor delivery efficiency; and thereby, enhancing imaging and therapeutic efficacy. Currently, polydopamine (PDA) attracts widespread attention because of its biocompatibility, simplicity of preparation, abundant surface groups, and high photothermal conversion efficiency, which can be applied in drug delivery, photothermal therapy, theranostics, and other nanomedicine fields. Inspired by PDA structures that are rich in catechol and amino functional groups that can coordinate with various metal ions, which have charming qualities and characteristics, metal-coordinated PDA structures are exploited for tumor theranostics, but are not thoroughly summarized. Herein, this review summarizes the recent progress in the fabrication of metal-coordinated PDA structures and their availabilities in tumor imaging and therapy, with further in-depth discussion of the challenges and future perspectives of metal-coordinated PDA structures, with the aim that this systematic review can promote interdisciplinary intersections and provide inspiration for the further growth and clinical translation of PDA materials., (© 2024 Wiley‐VCH GmbH.)

A bone defect refers to the loss of bone tissue caused by trauma or lesion. Bone defects result in high morbidity and deformity rates worldwide. Autologous bone grafting has been widely applied in clinics as the gold standard of treatment; however, it has limitations. Hence, bone tissue engineering has been proposed and developed as a novel therapeutic strategy for treating bone defects. Rapid and effective vascularization is essential for bone regeneration. In this study, a hierarchical composite scaffold with deferoxamine (DFO) delivery system, DFO@GMs-pDA/PCL-HNTs (DGPN), is developed, focusing on vascularized bone regeneration. The hierarchical structure of DGPN imitates the microstructure of natural bone and interacts with the local extracellular matrix, facilitating cell adhesion and proliferation. The addition of 1 wt% of halloysite nanotubes (HNTs) improves the material properties. Hydrophilic and functional groups conferred by polydopamine (pDA) modifications strengthen the scaffold bioactivity. Gelatin microspheres (GMs) protect the pharmacological activity of DFO, achieving local application and sustained release for 7 days. DFO effectively promotes angiogenesis by activating the signaling pathway of hypoxia inducible factor-1 α. In addition, DFO synergizes with HNTs to promote osteogenic differentiation and matrix mineralization. These results indicate that DGPN promotes bone regeneration and accelerates cranial defect healing., (© 2024 Wiley‐VCH GmbH.)

This work introduces rationally designed, improved amphiphilic single-chain polymer nanoparticles (SCNPs) for imaging and photodynamic therapy (PDT) in zebrafish embryo xenografts. SCNPs are ultrasmall polymeric nanoparticles with sizes similar to proteins, making them ideal for biomedical applications. Amphiphilic SCNPs result from the self-assembly in water of isolated synthetic polymeric chains through intrachain hydrophobic interactions, mimicking natural biomacromolecules and, specially, proteins (in size and when loaded with drugs, metal ions or fluorophores also in function). These ultrasmall, soft nanoparticles have various applications, including catalysis, sensing, and nanomedicine. Initial in vitro experiments with nonfunctionalized, amphiphilic SCNPs loaded with a photosensitizing Zn phthalocyanine with four nonperipheral isobutylthio substituents, ZnPc, showed promise for PDT. Herein, the preparation of improved, amphiphilic SCNPs containing ZnPc as highly efficient photosensitizer encapsulated within the nanoparticle and surrounded by anthracene units is disclosed. The amount of anthracene groups and ZnPc molecules within each single-chain nanoparticle controls the imaging and PDT properties of these nanocarriers. Critically, this work opens the way to improved PDT applications based on amphiphilic SCNPs as a first step toward ideal, long-term artificial photo-oxidases (APO)., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

The transformation of monotherapy into multimodal combined targeted therapy to fully exploit synergistic efficacy is of increasing interest in tumor treatment. In this work, a novel nanodrug-carrying platform based on iron-based MOFs, which is loaded with doxorubicin hydrochloride (DOX), dihydroartemisinin (DHA), and glucose oxidase (GOx), and concurrently covalently linked to the photosensitizer 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) in polydopamine (PDA)-encapsulated MIL-101(Fe) (denoted as MIL-101(Fe)-DOX-DHA@TCPP/GOx@PDA, MDDTG@P), is successfully developed. Upon entering the tumor microenvironment, MDDTG@P catalyzes the hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (·OH) and depletes glutathione (GSH); thus, exerting the role of chemodynamic therapy (CDT). The reduced Fe 2+ can also activate DHA, further expanding CDT and promoting tumor cell apoptosis. The introduced GOx will rapidly consume glucose and oxygen (O 2 ) in the tumor; while, replenishing H 2 O 2 for Fenton reaction, starving the cancer cells; and thus, realizing starvation and chemodynamic therapy. In addition, the covalent linkage of TCPP endows MDDTG@P with good photodynamic therapeutic (PDT) properties. Therefore, this study develops a nanocarrier platform for triple synergistic chemodynamic/photodynamic/starvation therapy, which has promising applications in the efficient treatment of tumors., (© 2024 Wiley‐VCH GmbH.)

Copper is indispensable to organisms, while its homeostatic imbalance may interference normal cellular physiological processes and even induce cell death. Artificially regulating cellular copper content provides a viable strategy to activate antineoplastic effect. In light of this, a copper ions homeostasis perturbator (CuP-CL) with cinnamaldehyde (Cin) packaging and thermosensitive liposome coating is reported. Following laser exposure, the doping of Cu 2+ in polydopamine initiates enhanced photothermal therapy (PTT) and unlocks the outer layer of liposome, leading to the release of copper ions and Cin in tumor microenvironment with mild acidity and high glutathione (GSH) levels. The liberative Cu 2+ can evoke cuproptosis and chemodynamic therapy (CDT). Meanwhile, leveraging the merits of H 2 O 2 supply and GSH consumption, Cin serves as a tumor microenvironment regulator to amplify Cu 2+ mediated cuproptosis and CDT. Additionally, the positive feedback effects of "laser-triggered PTT, PTT accelerates reactive oxygen species (ROS) generation, ROS amplifies lipid peroxide (LPO) accumulation, LPO mediates heat shock proteins (HSPs) clearance, down-regulated HSPs promote PTT" entailed the overall benefit to therapeutic outcomes. Both in vitro and in vivo results corroborate the remarkable antineoplastic performance of CuP-CL by the synergy of cuproptosis/CDT/PTT. Collectively, based on the three-pronged approach, this work plots a viable multimodal regimen for cancer therapy., (© 2024 Wiley‐VCH GmbH.)

Nitrogen (N 2 ) conversion to ammonia (NH 3 ) in a mild condition is a big chemical challenge. The whole-cell diazotrophs based biological NH 3 synthesis is one of the most promising strategies. Herein, the first attempt of photoelectrochemical-microbial (PEC-MB) biohybrid is contributed for artificial N 2 fixation, where Azotobacter vinelandii (A. vinelandii) is interfaced directly with polydopamine encapsulated nickel oxide (NiO) nanosheets (NiO@PDA). By virtue of excellent bio-adhesive activity, high conductivity, and good biocompatibility of PDA layer, abundant A. vinelandii are effectively adsorbed on NiO@PDA to form NiO@PDA/A. vinelandii biohybrid, and the rationally designed biohybrid achieved a record-high NH 3 production yield of 1.85   µmol h -1 /10 8 cells (4.14 µmol h -1 cm -2 ). In addition, this biohybrid can operate both under illumination with a PEC model or in dark with an electrocatalytic (EC) model to implement long-term and successional NH 3 synthesis. The enhancement mechanism of NH 3 synthesis in NiO@PDA/A. vinelandii biohybrid can be ascribed to the increase of nicotinamide adenine dinucleotide-hydrogen (NADH) and adenosine 5-triphosphate (ATP) concentrations and over expression of nitrogen-fixing genes of nifH, nifD and nifK in nitrogenase. This innovative PEC-MB biohybrid strategy sheds light on the fundamental mechanism and establishes proof of concept of biotic-abiotic photosynthetic systems for sustainable chemical production., (© 2024 Wiley‐VCH GmbH.)

Tuberculosis remains a leading cause of death from a single infection worldwide. Drug resistance to existing and even new antimycobacterials calls for research into novel targets and unexplored mechanisms of action. Recently we reported on the development of tight-binding inhibitors of Mycobacterium tuberculosis (Mtb) lipoamide dehydrogenase (Lpd), which selectively inhibit the bacterial but not the human enzyme based on a differential modality of inhibitor interaction with these targets. Here we report on the striking improvement in inhibitor residence time on the Mtb enzyme associated with scaffold progression from an indazole to 2-cyanoindole. Cryo-EM of Lpd with the bound 2-cyanoindole inhibitor 19 confirmed displacement of the buried water molecule deep in the binding channel with a cyano group. The ensuing hours-long improvement in on-target residence time is associated with enhanced antibacterial activity in axenic culture and in primary mouse macrophages. Resistance to 2-cyanoindole inhibitors involves mutations within the inhibitor binding site that have little effect on inhibitor affinity but change the modality of inhibitor-target interaction, resulting in fast dissociation from Lpd. These findings underscore that on-target residence time is a major determinant of antibacterial activity and in vivo efficacy., (© 2024 Wiley-VCH GmbH.)

Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3 a-d) and N-methyl-N-benzylamine (azaindoles 4 a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4 b and 4 c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives., (© 2024 Wiley-VCH GmbH.)

Reported herein is the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C-H oxygenation. The synthesis of the oxidation precursors was guided by recognition of an element of hidden symmetry. This work provides a foundation for the chemical synthesis of other poly-pseudoindoxyl alkaloids., (© 2024 Wiley-VCH GmbH.)

Ferroptosis in neurons is considered one of the key factors that induces Parkinson's disease (PD), which is caused by excessive iron accumulation in the intracellular labile iron pool (LIP). The iron ions released from the LIP lead to the aberrant generation of reactive oxygen species (ROS) to trigger ferroptosis and exacerbate PD progression. Herein, a pioneering design of multifunctional nanoregulator deferoxamine (DFO)-integrated nanosheets (BDPR NSs) is presented that target the LIP to restrict ferroptosis and protect against PD. The BDPR NSs are constructed by incorporating a brain-targeting peptide and DFO into polydopamine-modified black phosphorus nanosheets. These BDPR NSs can sequester free iron ions, thereby ameliorating LIP overload and regulating iron metabolism. Furthermore, the BDPR NSs can decrease lipid peroxidation generation by mitigating ROS accumulation. More importantly, BDPR NSs can specifically accumulate in the mitochondria to suppress ROS generation and decrease mitochondrial iron accumulation. In vivo experiments demonstrated that the BDPR NSs highly efficiently mitigated dopaminergic neuronloss and its associated behavioral disorders by modulating the LIP and inhibiting ferroptosis. Thus, the BDPR-based nanovectors holds promise as a potential avenue for advancing PD therapy., (© 2024 Wiley‐VCH GmbH.)

Traumatic brain injury (TBI) triggers inflammatory response and glial scarring, thus substantially hindering brain tissue repair. This process is exacerbated by the accumulation of activated immunocytes at the injury site, which contributes to scar formation and impedes tissue repair. In this study, a mussel-inspired nitric oxide-release microreservoir (MINOR) that combines the features of reactive oxygen species (ROS) scavengers and sustained NO release to promote angiogenesis and neurogenesis is developed for TBI therapy. The injectable MINOR fabricated using a microfluidic device exhibits excellent monodispersity and gel-like self-healing properties, thus allowing the maintenance of its structural integrity and functionality upon injection. Furthermore, polydopamine in the MINOR enhances cell adhesion, significantly reduces ROS levels, and suppresses inflammation. Moreover, a nitric oxide (NO) donor embedded into the MINOR enables the sustained release of NO, thus facilitating angiogenesis and mitigating inflammatory responses. By harnessing these synergistic effects, the biocompatible MINOR demonstrates remarkable efficacy in enhancing recovery in mice. These findings benefit future therapeutic interventions for patients with TBI., (© 2023 Wiley‐VCH GmbH.)

Liquid crystalline elastomers (LCEs) are a class of shape-changing polymers with exceptional mechanical properties and potential as artificial muscles/polymer actuators. In this study, multifunctional LCE actuators with strain sensing and joule heating responsivity are developed. LCEs are successfully synthesized using the thiol-ene two-staged michael addition polymerization (TMAP) method. The LCE films are further functionalized via sequential polydopamine (PDA) and silver electroless coating. It is found that the PDA coating enabled the anchoring of the Ag particles to the LCE, thereby enabling the electrical conductivity of the Ag-LCEs (<0.1 Ω cm -1 ). The studies confirm that the Ag/PDA coated LCEs can sense up to ≈30% strain, sense their own actuation strokes, and actuate at a rate of 1.83% s -1 while lifting a weight ≈50 times its mass in response to a 12 V 2A DC current., (© 2024 The Author(s). Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R 8 )-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R 8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8 + T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity., (© 2024 Wiley‐VCH GmbH.)

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC)., (© 2024 Wiley‐VCH GmbH.)

Lubricant-infused slippery surfaces have recently emerged as promising antifouling coatings, showing potential against proteins, cells, and marine mussels. However, a comprehensive understanding of the molecular binding behaviors and interaction strength of foulants to these surfaces is lacking. In this work, mussel-inspired chemistry based on catechol-containing chemicals including 3,4-dihydroxyphenylalanine (DOPA) and polydopamine (PDA) is employed to investigate the antifouling performance and repellence mechanisms of fluorinated-based slippery surface, and the correlated interaction mechanisms are probed using atomic force microscopy (AFM). Intermolecular force measurements and deposition experiments between PDA and the surface reveal the ability of lubricant film to inhibit the contact of PDA particles with the substrate. Moreover, the binding mechanisms and bond dissociation energy between a single DOPA moiety and the lubricant-infused slippery surface are quantitatively investigated employing single-molecule force spectroscopy based on AFM (SM-AFM), which reveal that the infused lubricant layer can remarkably influence the dissociation forces and weaken the binding strength between DOPA and underneath per-fluorinated monolayer surface. This work provides new nanomechanical insights into the fundamental antifouling mechanisms of the lubricant-infused slippery surfaces against mussel-derived adhesive chemicals, with important implications for the design of lubricant-infused materials and other novel antifouling platforms for various bioengineering and engineering applications., (© 2024 The Author(s). Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

The simultaneous application of photothermal therapy (PTT) and photodynamic therapy (PDT) offers substantial advantages in cancer treatment. However, their synergistic anticancer efficacy is often limited by tumor hypoxia, and thermotolerance induced by high expression of heat shock proteins (HSP). Fortunately, hydrogen sulfide (H 2 S), known for its direct cytotoxic effect on tumor cells, has been recognized for its ability to enhance PTT and PDT. The effectiveness of H 2 S in these therapies is challenged by its low loading efficiency, poor stability, and short diffusion distance. To address these issues, a nanoscale emulsion drop template created through the salting-out effect is employed to construct a robust H 2 S delivery system. Polydopamine (PDA), chosen for its interfacial polymerization tendency and excellent photothermal conversion rate, is utilized as a carrier for the H 2 S donor (ADT) and Zinc phthalocyanine (ZnPc) to fabricate a novel nanomedicine termed APZ NPs. The temperature-responsive APZ NPs are designed to release H 2 S during the PTT process. Elevated H 2 S levels promoted vasodilation, thereby enhancing the enhanced permeability and retention effect (EPR) of APZ NPs within solid tumors. This strategy effectively alleviated tumor hypoxia by disrupting the mitochondrial respiratory chain and mitigated tumor cell heat tolerance by inhibiting HSP expression., (© 2024 Wiley‐VCH GmbH.)

Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact mechanisms leading to cancer cell death. The indole-based WIN 55,212-2 and SDB-001 are both known as potent agonists at both CB 1 and CB 2 receptors, yet we demonstrate herein that only the former can exert in vitro antitumour effects when tested against a paediatric brain cancer cell line KNS42. In this report, we describe the synthesis of novel 3,4-fused tricyclic indoles and evaluate their functional potencies at both cannabinoid receptors, as well as their abilities to inhibit the growth or proliferation of KNS42 cells. Compared to our previously reported indole-2-carboxamides, these 3,4-fused tricyclic indoles had either completely lost activities, or, showed moderate-to-weak antagonism at both CB 1 and CB 2 receptors. Compound 23 displayed the most potent antitumour properties among the series. Our results further support the involvement of non-CB pathways for the observed antitumour activities of amidoalkylindole-based cannabinoids, in line with our previous findings. Transcriptomic analysis comparing cells treated or non-treated with compound 23 suggested the observed antitumour effects of 23 are likely to result mainly from disruption of the FOXM1-regulated cell cycle pathways., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Controlling infections while reducing the use of antibiotics is what doctors as well as researchers are looking for. As innovative smart materials, photothermal materials can achieve localized heating under light excitation for broad-spectrum bacterial inhibition. A polydopamine/chitosan/β-glycerophosphate temperature-sensitive hydrogel with excellent antibacterial ability is synthesized here. Initially, the hydrogel has good biocompatibility. In vitro experiments reveal its noncytotoxic property when cocultured with gingival fibroblasts and nonhemolytic capability. Concurrently, the in vivo biocompatibility is confirmed through liver and kidney blood markers and staining of key organs. Crucially, the hydrogel has excellent photothermal conversion performance, which can realize the photothermal conversion of hydrogel up to 3 mm thickness. When excited by near-infrared light, localized heating is attainable, resulting in clear inhibition impacts on both Staphylococcus aureus and Escherichia coli, with the inhibition rates of 91.22% and 96.69%, respectively. During studies on mice's infected wounds, it is observed that the hydrogel can decrease S. aureus' presence in the affected area when exposed to near-infrared light, and also lessen initial inflammation and apoptosis, hastening tissue healing. These findings provide valuable insights into the design of antibiotic-free novel biomaterials with good potential for clinical applications., (© 2024 Wiley‐VCH GmbH.)