Latest ArticlesThe employment of low-frequency electrical stimulation therapy has been shown to elicit a pronounced depolarization of neurons, thereby initiating the regenerative signaling cascades within neural cells, which is favorable for the regeneration of neural cells. In this study, we designed the flexible triboelectric nanogenerator device (TENG) to treat injury of peripheral nerve, which is combined with mesoporous silica (H-SiO2), high dielectric performance of polydimethylsiloxane (PDMS), and connected to biocompatible and conductive polycaprolactone (PCL) conduit materials for limited power generation to neuro-bioelectric response adaptation. By adjusting the content of H-SiO2 and the amount of PDMS monomers, the electrical performance of the device is optimized. Through the charge collection effect of silica molecular sieve, the endogenous neural electric field in nerve injury was stabilized, ensuring the consistency of the electrical stimulation level that is crucial for maintaining resting membrane potential. In vitro experiments clearly demonstrated that electrical stimulation derived from the triboelectric nanogenerator significantly promotes cell proliferation. Further animal experiments confirmed that electrical stimulation can effectively treat sciatic nerve injury and accelerate axonal regeneration. Based on experimental outcomes, we have developed an implantable sciatic nerve system that can stably generate effective electrical pulses in response to rat movement through charge collection. This system regulates the electric field around the injured sciatic nerve, maintains the electric field threshold required for rapid nerve tissue repair, and accelerates the recovery of nerve function.
The design and synthesis of fully conjugated covalent organic cages (cCOCs) featuring sp2 carbon connections pose significant challenges due to the difficulties associated with forming stable CC bonds. In this study, we present a novel anthracene-based cCOC linked by CC bonds, synthesized directly through Knoevenagel condensation. Remarkably, this sp2c COC has shown exceptional performance as an n-type semiconductor, characterized by strong electronic delocalization, an optimized band structure, and extensive light absorption capabilities. It efficiently catalyzes the photodegradation of organic dyes and promotes the photoinduced aerobic oxidation of amines to imines. In comparison to imine-linked cCOCs with the same skeleton, the sp2c COC demonstrates distinct advantages as a next-generation photocatalyst, including enhanced chemical stability and superior photocatalytic performance. This research underscores the potential of Knoevenagel condensation in the development of innovative cCOCs, offering valuable insights for their applications in optoelectronic materials and catalysis.
Peptides are increasingly favored as therapeutic agents due to their high efficacy, selectivity, and minimal side effects. However, they often face challenges related to poor stability and limited permeability through the gastrointestinal tract (GIT) and epithelia, necessitating parenteral administration. Despite this, there is a considerable demand for oral administration in clinical practice. To address the urgent clinical need for oral delivery, researchers have developed various technologies to surmount these challenges, including device-related systems, permeation enhancers (PEs), nanocarrier-based systems, and more. This review systematically explores the physiological barriers impacting peptide permeability and discusses the permeation-enhancing technologies designed to overcome them. It also reviews the oral peptide delivery systems currently available or under clinical investigation, offering insights into future developments in this field.
Electrochemically converting nitrate to ammonia under ambient conditions is a hot topic. However, it suffers from low efficiency because of the multi-electron/proton transfer. Herein, high-load atomic Fe (16.45 wt%) in-situ grown on carbon fiber cloth (Fe1@MoS2/CFC) demonstrates super high activity and selectivity in electrochemical nitrate reduction to ammonia at -0.73 V vs. RHE. The maximum NH3 yield is 28.59 mg h-1 cm-2, and the corresponding NH3-Faradaic efficiency is 96.65% at 360 mA/cm2 partial current density. The electrode exhibits good durability during ten cycled tests of 1 h each. The X-ray absorption near-edge structure (XANES), extended X-ray absorption fine structure (EXAFS), in-situ Raman analysis, and electron paramagnetic resonance (EPR) measurements reveal that the super high activity derives from the rich presence of active sites related to Fe-S and surrounding unsaturated Mo-S. Density functional theory (DFT) calculations show that the atomic Fe facilitates the water dissociation and provides sufficient active hydrogen for the edge Mo to boost nitrate reduction reaction (NO3-RR) activity, enhances NH3 selectivity, and decreases the energy barrier of NH3 desorption (rate-determining step) by regulating the coordination environment and electronic structure of the active Mo site. This stable and binder-free electrode with high dosage atomic Fe and rich edge Mo active sites is an attractive cathode for NO3-RR.
Photodynamic therapy (PDT) has attracted various attentions for cancer treatment, yet current strategies suffer many limitations including short retention time of photosensitizers, exacerbation of hypoxia due to oxygen consumption and restricted release of singlet oxygen under hypoxic conditions or in the absence of light. We present here a promising cancer therapy which not only reduces the frequency of drug administration and overall drug dosage through near-infrared (NIR) light-triggered drug immobilization in tumor sites, but also enhances anticancer efficacy by synergistic treatments through PDT and chemotherapeutic drug camptothecin. More importantly, endoperoxides generated in situ can not only persistently release singlet oxygen even in the absence of light, thereby augmenting PDT efficacy, but also release triplet oxygen to alleviate tumor hypoxia exacerbated by PDT. Its enhanced retention time was demonstrated both in vitro (96 h) and in vivo (240 h), with the duration adjustable by varying the light source. Notably, a single administration (3 mg/mL, 300 µL) during the entire treatment under low-power red light irradiation (11 mW/cm2) resulted in efficient suppression of the tumor growth and pulmonary metastasis. This NIR light-triggered long-acting platforms could be utilized for design of long-term disease imaging and therapy tools, and the in situ generated endoperoxide is promising for self-regulation of tumor hypoxia.
Estrogen sulfotransferase (SULT1E1), an essential conjugative enzyme in mammals, plays a crucial role in both estrogen homeostasis and xenobiotic metabolism. Deciphering the dynamic changes in SULT1E1 function under specific physiological or pathological conditions and discovering SULT1E1 modulators require practical and highly efficient tools for sensing SULT1E1 in biological context. Herein, we showcase a scaffold-seeking and structural optimization strategy for the rational engineering of isoform-specific fluorescent substrates for SULT1E1. First, docking-based virtual screening coupled with biochemical assays suggested that N-butyl-4-hydroxyphenyl-1,8-naphthalimide (HPN) was a suitable scaffold for constructing the fluorescent substrates for SULT1E1, but this fluorophore could be metabolized by multiple SULT isoforms. To develop isoform-specific substrates for SULT1E1, various substituents were introduced on the north part of HPN to explore the structure-enzyme specificity relationships of HPN derivatives as SULT1E1 substrates. After molecular docking and experimental validation, an isoform-specific fluorescent substrate (HPN10) for SULT1E1 was successfully engineered. HPN10 demonstrated exceptional isoform-specificity, ultra-high sensitivity, and favorable signal-to-noise ratio (212). HPN10 excelled in the precise sensing of SULT1E1 activities in complex biological matrices, including cellular specimens and liver preparations. HPN10 immensely facilitated the discovery and characterization of SULT1E1 inhibitors, while tetrabromobisphenol A (TBBPA, half inhibitory concentration (IC50) = 31.5 ± 3.4 nmol/L) was identified as a potent SULT1E1 inhibitor that could strongly block SULT1E1 activities in living cells. Collectively, this work presents a practical and efficient strategy for the rational engineering of isoform-specific fluorescent substrates for target conjugative enzyme(s), while HPN10 emerges as a reliable SULT1E1-activatable tool for functional sensing and drug discovery.
Mucosal vaccines would be game-changing for blocking pathogenic transmission, prompting protection where microorganism first enters that those intramuscular ones could not be able to achieve. The exploration of the vaccines at mucosal surfaces is gaining momentum due to the unique immune reservoir they offer in a minimally invasive manner. Nevertheless, the application of mucosal vaccines faces challenges, including barriers such as degrading enzymes, mucus interference, and clearance mechanisms. The field of mucosal vaccination is still in its early stages, and its advancement will significantly benefit from foundational inquiries into immune activation mechanisms and the innovation of delivery technologies for optimal efficacy. It is highly central to design efficient systems for mucosal vaccine development, herein, this article offers the insights towards the status, bottlenecks and solutions in this field, the intricacies of the immune response, fundamental mechanisms, applications of the delivery strategies for various forms of mucosal vaccines are explored. Collectively, this review conducts systematical analysis on biological and chemical strategies designed to augment vaccine uptake across mucosal tissues, antigen design and delivery methods strengthening vaccination efficacy, with emphasis on the emerging mRNA mucosal vaccines, offering new insights into recent advancements, trends and future scenarios, aiming to harness mucosal immunity (MI) for comprehensive protection against infections and other diseases.
Given the immense potential of sonodynamic therapy (SDT) in cancer treatment, designing effective sonosensitizers (SNSs) and elucidating their mechanisms are crucial for advancing the field and enhancing anti-tumor responses. However, there are still several limitations that hinder the application of SDT, such as the activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Herein, we designed an endoplasmic reticulum (ER)-targeted iridium(Ⅲ) SNS, C6IrAC, which exhibits specific toxicity towards tumor cells and excellent performance as a SNS. C6IrAC specifically targets the ER, causing ER stress, and under ultrasound (US) stimulation, the increased stress intensity enhances therapeutic efficacy. C6IrAC induces the degradation of HIF-1α and suppresses the HIF-1 pathway, thereby enhancing SDT. Furthermore, C6IrAC-induced ER stress leads to mitochondrial calcium overload, which subsequently results in the release of a large amount of mitochondrial DNA (mtDNA) into the cytoplasm, thereby activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Significant anti-tumor effects have been consistently observed both in vitro and in vivo. C6IrAC can effectively activate both the innate and adaptive immune systems, highlighting its substantial therapeutic potential. Taken together, this study provides a feasible method to overcome the limitations of SDT, and opens up new avenues for the design of SNSs.
Glioma, a highly aggressive brain tumor with a dismal prognosis, faces significant treatment hurdles due to the blood-brain barrier, which limits the efficient delivery of most medications. Diphtheria toxin receptor (DTR) is a specific receptor expressed both on brain microvascular endothelial cells and glioma, emerging as a potentially valuable target for targeted drug delivery system for glioma treatment. In this work, a short peptide (designated DTX) derived from diphtheria toxin, was rational designed and chemical synthesized based on the binding domain to DTR. The function of DTX as a ligand of DTR and the brain/glioma dual targeting efficacy were evaluated in vitro and in vivo. Furthermore, DTX was conjugated to vorinostat (SAHA) to enable its anti-glioma efficacy. The results demonstrated that DTX-SAHA can effectively cross the blood-brain barrier, exhibiting promising anti-glioma efficacy with good biocompatibility. This research confirmed the potential of DTX as the ligand for DTR-mediated intracranial drug delivery.
A new type of C2-symmetric chiral spirobiindole structure is developed, and excellent diastereoselectivities and enantioselectivities (>20:1 dr & >99% ee for all examples) were obtained via an asymmetric rhodium catalysis-intramolecular spirocyclization sequence. Selective synthesis of both spirobiindole enantiomers could be achieved using the same catalyst by simply switching the substrate combination.
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