Cleavage Of Disulfide Bonds Research Articles

Comparison of Cell-Penetrating and Fusogenic TAT-HA2 Peptide Performance in Peptideplex, Multicomponent, and Conjugate siRNA Delivery Systems.

In this study, the performance of the cell-penetrating and fusogenic peptide, TAT-HA2, which consists of a cell-permeable HIV trans-activator of transcription (TAT) protein transduction domain and a pH-responsive influenza A virus hemagglutinin protein (HA2) domain, was comparatively evaluated for the first time in peptideplex, multicomponent, and conjugate siRNA delivery systems. TAT-HA2 in all three systems protected siRNA from degradation, except in the conjugate system with a low Peptide/siRNA ratio. The synergistic effect of different peptide domains enhanced the transfection efficiency of multicomponent and conjugate systems compared to that of peptideplexes, which was attributed to the surface configuration of TAT-HA2 peptides depending on the nature of attachment. Particularly, the multicomponent system showed better cellular uptake and endosomal escape than the peptideplexes, resulting in enhanced siRNA delivery in the cytoplasm. In addition, the presence of cleavable disulfide bonds in multicomponent and conjugate systems promoted the effective siRNA delivery in the cytoplasm, resulting in improved gene silencing activity. The multicomponent system reduced the level of luciferase expression in SKOV3 cells to 45% (±4). In contrast, the conjugate system and the commercially available siRNA transfection agent, Lipofectamine RNAiMax, caused luciferase suppression down to 55% (±2) at a siRNA dose of 100 nM. For the same dose, the peptideplex system could only reduce the luciferase expression to 65% (±5). None of the developed systems showed significant toxicity at any dose. Overall, the TAT-HA2 peptide is promising as a siRNA delivery vector; however, its performance depends on the nature of attachment and, as a result, its surface configuration on the developed delivery system.

Structural analysis of a ligand-triggered intermolecular disulfide switch in a major latex protein from opium poppy.

Several proteins from plant pathogenesis-related family 10 (PR10) are highly abundant in the latex of opium poppy and have recently been shown to play diverse and important roles in the biosynthesis of benzylisoquinoline alkaloids (BIAs). The recent determination of the first crystal structures of PR10-10 showed how large conformational changes in a surface loop and adjacent β-strand are coupled to the binding of BIA compounds to the central hydrophobic binding pocket. A more detailed analysis of these conformational changes is now reported to further clarify how ligand binding is coupled to the formation and cleavage of an intermolecular disulfide bond that is only sterically allowed when the BIA binding pocket is empty. To decouple ligand binding from disulfide-bond formation, each of the two highly conserved cysteine residues (Cys59 and Cys155) in PR10-10 was replaced with serine using site-directed mutagenesis. Crystal structures of the Cys59Ser mutant were determined in the presence of papaverine and in the absence of exogenous BIA compounds. A crystal structure of the Cys155Ser mutant was also determined in the absence ofexogenous BIA compounds. All three of these crystal structures reveal conformations similar to that of wild-type PR10-10 with bound BIA compounds. In the absence of exogenous BIA compounds, the Cys59Ser and Cys155Ser mutants appear to bind an unidentified ligand or mixture of ligands that was presumably introduced during expression of the proteins in Escherichia coli. The analysis of conformational changes triggered by the binding of BIA compounds suggests a molecular mechanism coupling ligand binding to the disruption of an intermolecular disulfide bond. This mechanism may be involved in the regulation of biosynthetic reactions in plants and possibly other organisms.

Contribution of yeast freezing to the quality of frozen dough: Rheological properties, protein depolymerization, gluten conformation and water state

The present study has comparatively investigated the variation in yeast leachates in frozen suspension and dough systems and assessed the effects of leachate released from frozen yeast cells on dough rheology, protein molecular weight distribution, gluten conformation, and water state. The results revealed that yeast in the dough was more susceptible to freezing than that in the suspension and released more low-molecular-weight metabolites (e.g., trehalose, glutathione, and amino acids) into the dough matrix. Dynamic rheological measurements showed that frozen yeasted dough had weaker viscoelastic properties than non-yeasted dough. Fourier transform infrared spectroscopy revealed a high fraction of β-turns and random coils at the expense of α-helices and β-sheets, demonstrating a flexible protein secondary structure and increase in weakened hydrogen bonds in the gluten network. The presence of yeast in the frozen dough facilitated dough depolymerization via the cleavage of interchain disulfide bonds of gluten protein and softened the gluten network structure. Yeast leachates released from frozen yeast cells caused water redistribution in the dough and increased water release from the weakened gluten network, increasing freezable water content. This study has revealed the essential role of yeast freezing in gluten depolymerization and the deterioration of dough quality.

Disulfide bond cleavage combined with critical pH induced unfolding and assembly of soy protein and its encapsulation effect on curcumin

The limited water solubility and bioactivity of hydrophobic phytochemicals can be improved and preserved by encapsulation technologies. In this research, a low-cost and low-energy encapsulation method was explored based on the self-assembly characteristics of soy protein (SP). The disulfide bond of SP was broken by Na2S2O5, and then the pH of SP was adjusted to the critical pH 10.5 with NaOH, which was the critical point of protein unfolding. The treated protein was added to curcumin (Cur), which was encapsulated in self-assembled protein nanoparticles during the subsequent neutralization process to obtain the soy protein-curcumin complex (SP-Cur). This process was known as the disulfide bond breaking combined with critical pH-driven technology. The cleavage of SP disulfide bonds was studied by the methods of 4, 4′-dithiopyridine (DPS) and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). When the SP:Cur mass ratio was 1:1, the encapsulation efficiency (EE%) of Cur in SP-Cur obtained by disulfide bond breaking combined with the critical pH-driven method increased to 85.36 ± 1.03%. It was notably greater than the EE% of Cur in SP-Cur prepared by the pH-driven method (61.82 ± 1.54%) and the EE% of Cur in SP-Cur prepared by disulfide bond breaking treatment (66.38 ± 1.2%). The encapsulation of Cur in SP particles exhibited significant resistance to light and temperature, leading to enhanced stability. Soy protein treated with disulfide bond cleavage combined with critical pH-driven method can serve as a potential functional carrier to further incorporate hydrophobic compounds into food systems.

Amphiphilic Affibody-PROTAC conjugate Self-Assembled nanoagents for targeted cancer therapy

Proteolysis-targeting chimeras (PROTACs) are an emerging class of promising therapeutic molecules that can target specific disease-related proteins and then degrade them by the cellular ubiquitin–proteasome system. However, the excessive hydrophobicity and potential off-target effects of PROTACs severely limit their applications in clinics. In this work, we constructed a targeting nano-delivery system to improve the biological availability of PROTACs. A hydrophilic affibody ZEGFR:1907 (an affinity protein of epidermal growth factor receptor, EGFR) was selected to couple with a hydrophobic drug PROTAC MS28 (a cyclin D1 degrader) through a bio-responsive linker containing disulfide bond to produce an amphiphilic ZEGFR:1907-MS28 conjugate. It was able to self-assemble into a nanoagent (ZEGFR:1907-MS28 ADCN) in PBS for targeted cancer therapy. Benefiting from the extraordinary targeting performance of ZEGFR:1907, ZEGFR:1907-MS28 ADCN can be effectively accumulated in tumor sites through the EGFR-mediated endocytosis. After internalization in vitro, ZEGFR:1907-MS28 ADCN released PROTAC MS28 via the cleavage of disulfide bonds at the high level of glutathione to selectively degrade cyclin D1 and then induced apoptosis of cancer cells. After tail-vein injection in vivo, ZEGFR:1907-MS28 ADCN also exhibited significant tumor selectivity, favorable biological safety, excellent cyclin D1 degradation and good antitumor activity in EGFR-positive epidermal carcinoma tumor models. In summary, this affibody mediated nano-delivery system would provide a versatile platform for the application of PROTACs in targeted cancer therapy.

Erythrocyte membrane-camouflaged nanodelivery strategy enhances gene editing efficiency of Cas9 RNP for boosting tumor senescence

CRISPR-Cas9 system has emerged as an effective tool for sequence-specific gene knockout through non-homologous end joining (NHEJ). However, the inefficient precise editing of genome sequences remains a challenge for clinical treatment. Herein, an erythrocyte membrane (EM)-camouflaged and tumor microenvironment (TME)-responsive nanosystem was constructed to achieve synergistic combination of enhanced Cas9 ribonucleoprotein (RNP) gene editing efficiency and telomere dysfunction, and thus precise induced tumor inhibition. The EM-camouflaged nanosystem escaped from the reticuloendothelial system (RES) and was endocytosed by tumor cells. Azidothymidine (AZT) was gradually released as the erythrocyte shell ablation, which competitively prevented the binding of single nucleotides to the telomere replication template TR, terminate the extension of the telomerase DNA chain. Additionally, Cas9 RNP was released through disulfide bond cleavage and entered into the nucleus to realize genome editing of telomerase reverse transcriptase (TERT) gene. Simultaneous, AZT enhanced NHEJ pathway to improve the gene editing efficiency of Cas9 RNP, which further promoted the progressive telomere erosion and thus induced tumor inhibition. Overall, this biomembrane-camouflaged nanosystem realizes enhanced Cas9 RNP gene editing efficiency with high-level biosafety and promotes tumor senescence by triggering telomere disorder, which provides strategy for improving the gene editing efficiency to induce senescence of tumor cells.

Biomimetic Remineralization of Dental Hard Tissues via Amyloid‐Like Protein Matrix Composite with Amorphous Calcium Phosphate

AbstractNumerous remineralizing coatings aim to prevent or treat early enamel lesions and occlude exposed dentinal tubules (DTs). Nevertheless, the pace of remineralization is inadequate, and the mechanical robustness of the newly established mineral layer fails to match the inherent strength. In this study, a biomimetic mineralization strategy aimed at replicating key events in biological mineralization, specifically focusing on the organic–inorganic composite matrix, is proposed. The material utilizes Tris(2‐carboxyethyl)phosphine (TCEP), which serves a dual role: stabilized amorphous calcium phosphate (ACP) (ACP@TCEP) nanoparticles as its inorganic component, and catalyzing the cleavage of intramolecular disulfide bonds in poly(ethylene glycol) (PEG) grafted lysozyme (lyso‐PEG) to facilitate the formation of an amyloid‐like protein matrix composite with ACP (ACP@lyso‐PEG nanocomplexes). ACP@lyso‐PEG nanocomplexes can rapidly and efficiently form an enamel‐like remineralization layer on the surface of damaged dental hard tissue, reaching ≈4.205 µm thickness after 3 days of acid‐etched enamel. Furthermore, achieving a depth of DTs occlusion exceeding 60 µm after 5 days, using a simple immersion process. The resulting mineralized layer exhibits mechanical strength comparable to natural teeth. This study introduces a conceptual biomimetic mineralization strategy for effective enamel repair or DTs occlusion in clinical practices, and offers potential insights into the mechanisms of biomineral formation.

A Redox-Triggered Autophagy-Induced Nanoplatform with PD-L1 Inhibition for Enhancing Combined Chemo-Immunotherapy.

Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.

High barrier polyesters based on 2,5-furandicarboxylic acid and disulfide bond: Smart degradation induced by low concentrations of redox reagent

Bio-based and biodegradable polymers opens up opportunities to overcome resource depletion and plastic pollution. However, the degradation mechanism based on ester bond breakage makes it difficult to achieve controllable degradation induced by external stimuli. In this work, we present a new 2,5-furandicarboxylic acid-based copolyesters (PBFDi) by partially replacing carbon–carbon backbones with disulfide bonds and discuss the influence of disulfide bonds on thermal stability, crystallization behavior, mechanical and barrier properties of polyesters. They could maintain stable for 1 h at processing temperatures of 220 °C, meeting the needs of long-term melt processing. The asymmetric structure of the furan ring and the slower free rotation of disulfide bonds help restrict the mobility of chains and obstruct gas permeation, resulting in 9.3–126.7 times increase in O2 barrier than commercial PBAT. With the introduction of small amount (≤40 %) of disulfide bond units, the hydrolysis rate is relatively slow and can maintain stable during storage and use. As expected, the copolyesters show redox dual-responsive degradation. Even at low concentrations (0.01 M and 0.1 M) of H2O2, the transition from hydrophobicity to hydrophilicity can be achieved, expected to accelerate the hydrolysis of PBFDi. The fast cleavage of disulfide bonds induced by DTT could be influenced by the copolymerized FDCA units. Lastly, the redox dual-responsive mechanism is elucidated, and how the rigid FDCA co-monomers affect the redox dual responsiveness is also clarified.

Elucidating the Degradation Pathways of Human Insulin in the Solid State

While there have been significant advances in the development of peptide oral dosage forms in recent years, highlighted by the clinical and commercial success of approved peptides such as Rybelsus®, there remain several barriers in the way of broad range applicability of this approach to peptide delivery. One such barrier includes the poor physical and chemical stability inherent to their structures, which persists in the solid state although degradation typically occurs at different rates and via different pathways in comparison to the solution state. Using insulin as a model peptide, this work sought to contribute to the development of analytical techniques for investigating common insulin degradation pathways. Chemically denatured, deamidated and aggregated samples were prepared and used to benchmark circular dichroism spectroscopy, reverse phase HPLC and size exclusion chromatography methods for the investigation of unfolding, chemical modifications and covalent aggregation of the insulin molecule respectively. Solid state degraded samples were prepared by heating insulin powder at 60 °C and 75% relative humidity for 1, 3, 5 and 7 d, and the degradation profiles of the samples were evaluated and compared with those observed in solution. While no unfolding was observed to occur, significant deamidation and covalent aggregation were detected. Reductive disulfide bond cleavage using dithiothreitol allowed for separation of the insulin A- and B-chains, offering a facile yet novel means of assessing the mechanisms of deamidation and covalent aggregation occurring in the solid state.

Dual pH/redox-responsive hyperbranched polymeric nanocarriers with TME-trigger size shrinkage and charge reversible ability for amplified chemotherapy of breast cancer

A novel pH/redox-responsive hyperbranched MeO-PEG-b-(NIPAAm-co-PBAE) nanoparticles (NPs) were designed with size shrinkage and charge-reversible potential for targeted delivery of docetaxel (DTX) to MDA-MB-231 cell lines. In the tumor microenvironment (TME), amine protonation induces charge reversal and disulfide bond cleavage under high TME GSH concentration causing size shrinkage, improved deep tumor penetration, and active targeting of the therapeutic agents. These nano drug delivery systems (NDDSs) significantly promoted cancer cell uptake (~ 100% at 0.5 h), facilitating site-specific delivery and deep tumor penetration. The MTT assay revealed significantly higher cytotoxicity (P value < 0.0001) for DTX-loaded NPs compared to free DTX. Cell cycle analysis revealed G2/M (58.3 ± 2.1%) and S (21.5 ± 1.3%) arrest for DTX-loaded NPs, while free DTX caused G2/M (67.9 ± 1.1%) and sub-G1 (10.3 ± 0.8%) arrest. DTX-loaded NPs induced higher apoptosis (P value < 0.001) in MDA-MB-231 cells (71.5 ± 2.8%) compared to free DTX (42.3 ± 3.1%). Western blotting and RT-PCR assays confirmed significant up-regulation of protein levels and apoptotic genes by DTX-loaded NPs compared to free DTX. In conclusion, TME-responsive charge reversal and size-shrinkable smart NDDSs designed based on low pH, and high glutathione (GSH), offer more effective site-specific delivery of therapeutic agents to tumors.

Injectable composite hydrogels embedded with gallium-based liquid metal particles for solid breast cancer treatment via chemo-photothermal combination

Photothermal therapy (PTT) holds great promise as a cancer treatment modality by generating localized heat at the tumor site. Among various photothermal agents, gallium-based liquid metal (LM) has been widely used as a new photothermal-inducible metallic compound due to its structural transformability. To overcome limitations of random aggregation and dissipation of administrated LM particles into a human body, we developed LM-containing injectable composite hydrogel platforms capable of achieving spatiotemporal PTT and chemotherapy. Eutectic gallium–indium LM particles were first stabilized with 1,2-Distearoyl-sn‑glycero-3-phosphoethanolamine (DSPE) lipids. They were then incorporated into an interpenetrating hydrogel network composed of thiolated gelatin conjugated with 6-mercaptopurine (MP) chemodrug and poly(ethylene glycol)-diacrylate. The resulted composite hydrogel exhibited sufficient capability to induce MDA-MB-231 breast cancer cell death through a multi-step mechanism: (1) hyperthermic cancer cell death due to temperature elevation by near-infrared laser irradiation via LM particles, (2) leakage of glutathione (GSH) and cleavage of disulfide bonds due to destruction of cancer cells. As a consequence, additional chemotherapy was facilitated by GSH, leading to accelerated release of MP within the tumor microenvironment. The effectiveness of our composite hydrogel system was evaluated both in vitro and in vivo, demonstrating significant tumor suppression and killing. These results demonstrate the potential of this injectable composite hydrogel for spatiotemporal cancer treatment. In conclusion, integration of PTT and chemotherapy within our hydrogel platform offers enhanced therapeutic efficacy, suggesting promising prospects for future clinical applications. Statement of significanceOur research pioneers a breakthrough in cancer treatments by developing an injectable hydrogel platform incorporating liquid metal (LM) particle-mediated photothermal therapy and 6-mercaptopurine (MP)-based chemotherapy. The combination of gallium-based LM and MP achieves synergistic anticancer effects, and our injectable composite hydrogel acts as a localized reservoir for specific delivery of both therapeutic agents. This platform induces a multi-step anticancer mechanism, combining NIR-mediated hyperthermic tumor death and drug release triggered by released glutathione from damaged cancer populations. The synergistic efficacy validated in vitro and in vivo studies highlights significant tumor suppression. This injectable composite hydrogel with synergistic therapeutic efficacy holds immense promise for biomaterial-mediated spatiotemporal treatment of solid tumors, offering a potent targeted therapy for triple negative breast cancers.

Tumor microenvironment‐responsive hyaluronic acid‐oxaliplatin nanoparticles enhanced tumor cell elimination

AbstractOxaliplatin (OXA) is widely utilized in clinical cancer treatment, however its effectiveness is hindered by drug resistance and severe side effects resulting from non‐targeted delivery and lack of response to the tumor environment. In this research, thiol modified OXA and oligo hyaluronic acid (oHA) were used to developed a redox‐responsive OXA‐SS‐oHA nanoparticle delivery system. The nanoparticles could release oxaliplatin prodrug OXA‐SH through the cleavage of disulfide bonds in response of the abundant GSH in the tumor environment. OXA‐SS‐oHA nanoparticles were stable in aqueous solution for 7 days, and in vitro release experiments showed that the cumulative release of OXA in the absence of GSH was 21%, while in the presence of 10 mM concentration of GSH, the cumulative release was 47%. Additionally, OXA‐SS‐oHA demonstrated greater efficacy in inducing cell death in GSH‐positive cells (MKN45) when compared to GSH‐negative cells (L929). This study provides a novel strategy for the construction of GSH‐stimulated responsive targeted drug delivery systems for cancer therapy.

Unveiling the Properties of Sulfhydryl Groups in a Single-Molecule Junction.

The metal-thiol interface is ubiquitous in nanotechnology and surface chemistry. It is not only used to construct nanocomposites but also plays a decisive role in the properties of these materials. When organothiol molecules bind to the gold surface, there is still controversy over whether sulfhydryl groups can form disulfide bonds and whether these disulfide bonds can remain stable on the gold surface. Here, we investigate the intrinsic properties of sulfhydryl groups on the gold surface at the single-molecule level using a scanning tunneling microscope break junction technique. Our findings indicate that sulfhydryl groups can react with each other to form disulfide bonds on the gold surface, and the electric field can promote the sulfhydryl coupling reaction. In addition to these findings, ultraviolet irradiation is used to effectively regulate the coupling between sulfhydryl groups, leading to the formation and cleavage of disulfide bonds. These results unveil the intrinsic properties of sulfhydryl groups on the gold surface, therefore facilitating the accurate construction of broad nanocomposites with the desired functionalities.

Reversibly Cross-Linked Isoporous Membranes Fabricated by the Recyclable Block Copolymer with Pendent Dithiolane Groups.

The reversible formation and cleavage of disulfide bonds under physical/chemical stimuli make it a valuable motif in constructing dynamically cross-linked materials. In the present work, the block copolymer bearing pendent dithiolanes was synthesized and fabricated into isoporous membranes by the combination of self-assembly and nonsolvent-induced phase separation strategy. The cross-linking within the membrane was realized by the thiol-initiated ring-opening cascades of cyclic disulfides. Successful formation of disulfide bond networks within the isoporous membranes was proved by the Raman spectra, UV-vis diffuse reflectance spectroscopy, differential scanning calorimetry, and rheological analysis. The cross-linking in membranes was further demonstrated by the notably improved toughness and obviously enhanced swelling resistance to acid/alkaline solution as well as organic solvents. Importantly, the cross-linked isoporous membranes were fully dissolvable in solution containing dithiothreitol, which enabled the complete cleavage of disulfide bonds and successful recovery of the block copolymer that was able to be repeatedly fabricated into isoporous membranes with pore sizes identical to membranes prepared from the freshly synthesized copolymer. Our results indicate that dynamically cross-linked isoporous membranes with improved durability and good recyclability can be custom-made by simply incorporating active dithiolane moieties into self-assembling block copolymers.

PEGylated AIEgens for dual sensing of ATP and H2S and cancer cells photodynamic therapy

Fluorescent sensors have been widely applied for biosensing, but probes for both multiple analytes sensing and photodynamic therapy (PDT) effect are less reported. In this article, we reported three AIE-based probes anchored with different mass-weight polyethylene glycol (PEG) tails, i.e., TPE-PEG160, TPE-PEG350, and TPE-PEG750, for both adenosine-5′-triphosphate (ATP) and hydrogen sulfide (H2S) detection and also cancer cells photodynamic therapy. TPE-PEGns (n = 160, 350 and 750) contain the tetraphenylethylene-based fluorophore core, the pyridinium and amide anion binding sites, the H2S cleavable disulfide bond, and the hydrophilic PEG chain. They exhibit a good amphiphilic property and can self-assemble nona-aggregation with a moderated red emission in an aqueous solution. Importantly, the size of aggregation, photophysical property, sensing ability and photosensitivity of these amphiphilic probes can be controlled by tuning the PEG chain length. Moreover, the selected probe TPE-PEG160 has been successfully used to detect environmental H2S and image ATP levels in living cells, and TPE-PEG750 has been used for photodynamic therapy of tumor cells under light irradiation.

Supramolecular prodrug-like nanotheranostics with dynamic and activatable nature for synergistic photothermal immunotherapy of metastatic cancer

Synergistic photothermal immunotherapy has attracted widespread attention due to the mutually reinforcing therapeutic effects on primary and metastatic tumors. However, the lack of clinical approval nanomedicines for spatial, temporal, and dosage control of drug co-administration underscores the challenges facing this field. Here, a photothermal agent (Cy7-TCF) and an immune checkpoint blocker (NLG919) are conjugated via disulfide bond to construct a tumor-specific small molecule prodrug (Cy7-TCF-SS-NLG), which self-assembles into prodrug-like nano-assemblies (PNAs) that are self-delivering and self-formulating. In tumor cells, over-produced GSH cleaves disulfide bonds to release Cy7-TCF-OH, which re-assembles into nanoparticles to enhance photothermal conversion while generate reactive oxygen species (ROSs) upon laser irradiation, and then binds to endogenous albumin to activate near-infrared fluorescence, enabling multimodal imaging-guided phototherapy for primary tumor ablation and subsequent release of tumor-associated antigens (TAAs). These TAAs, in combination with the co-released NLG919, effectively activated effector T cells and suppressed Tregs, thereby boosting antitumor immunity to prevent tumor metastasis. This work provides a simple yet effective strategy that integrates the supramolecular dynamics and reversibility with stimuli-responsive covalent bonding to design a simple small molecule with synergistic multimodal imaging-guided phototherapy and immunotherapy cascades for cancer treatment with high clinical value.

Low swelling Alginate/Lignin network gels with redox responsiveness for sustained release of agricultural fungicide and Pb2+ complexation

Fungicides are among the most essential agrochemicals for controlling crop diseases. However, the increased consumption of fungicides has resulted in environmental pollution and adversely affected human health. The slow-release technology can improve the efficacy and reduce the required amount of fungicide. Here, we developed a low-swelling redox-responsive alginate/lignin network bearing covalently conjugated fungicide thymol-Cl. Natural reductants in the environment caused the selective cleavage of disulfide bonds and release of thymol-Cl and thiazolidin-2-one (a by-product), which both could inhibit the phytopathogenic fungus (F. oxysporum). At the same time, metal chelating groups in the gel endow strong interactions with heavy metal ions for improving soil remediation and preventing the adsorption of toxic metals by the plant roots. The fungicide-loaded carrier could alleviate the poisonous effect of fungi on maize seeds. Indeed, the secretion of natural reducing agents by fungi and maize led to the cleavage of disulfide bonds and the release of fungicides.

GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy.

Bacterial biofilm infection threatens public health, and efficient treatment strategies are urgently required. Phototherapy is a potential candidate, but it is limited because of the off-targeting property, vulnerable activity, and normal tissue damage. Herein, cascade-responsive nanoparticles (NPs) with a synergistic effect of phototherapy and chemotherapy are proposed for targeted elimination of biofilms. The NPs are fabricated by encapsulating IR780 in a polycarbonate-based polymer that contains disulfide bonds in the main chain and a Schiff-base bond connecting vancomycin (Van) pendants in the side chain (denoted as SP-Van@IR780 NPs). SP-Van@IR780 NPs specifically target bacterial biofilms in vitro and in vivo by the mediation of Van pendants. Subsequently, SP-Van@IR780 NPs are decomposed into small size and achieve deep biofilm penetration due to the cleavage of disulfide bonds in the presence of GSH. Thereafter, Van is then detached from the NPs because the Schiff base bonds are broken at low pH when SP@IR780 NPs penetrate into the interior of biofilm. The released Van and IR780 exhibit a robust synergistic effect of chemotherapy and phototherapy, strongly eliminate the biofilm both in vitro and in vivo. Therefore, these biocompatible SP-Van@IR780 NPs provide a new outlook for the therapy of bacterial biofilm infection.

Complete amide cis-trans switching synchronized with disulfide bond formation and cleavage in a proline-mimicking system.

A typical naturally occurring disulfide structure in proteins is an 8-membered disulfide ring formed between two adjacent cysteine (Cys-Cys) residues. Based on this structure, we designed 7- to 9-membered disulfide ring molecules, embedded in the 7-azabicyclo[2.2.1]heptane skeleton, that switch their conformation from exclusively trans-amide to exclusively cis-amide upon redox transformation from dithiol to disulfide, and vice versa. Constrained shape of disulfide rings is rare in nature, and the present molecular structure is expected to be a useful fundamental component for the construction of new conformation-switching systems.