Latest ArticlesThe poor biofilm colonization, charge transfer, and storage at the anode have long been major obstacles to achieving high power generation in bioelectrochemical systems (BES). To overcome this challenge, we developed electrospun carbon nanofiber-interpenetrated reduced graphene oxide aerogels (CNF/rGO-x, where x denotes the mass ratio of CNF to rGO, with x = 2, 4, 6) to modify the surface of carbon cloth (CC), significantly enhancing its electrochemical performance. The CNF/rGO-6 aerogel featured a porous, interconnected conductive scaffold, endowing the CC electrode with a larger electrochemically active area, higher specific capacitance, and a rougher surface. These properties significantly improved biofilm adhesion, extracellular electron transfer, and charge storage capabilities. As a result, the BES equipped with a CNF/rGO-6 electrode achieved an impressive power density of 3080.3 mW/m2, significantly higher than those of BES with CNF/rGO-4 (2426.3 mW/m2), CNF/rGO-2 (2717 mW/m2), rGO (1978.3 mW/m2), and pure CC (1050.4 mW/m2) electrodes. Furthermore, the CNF/rGO-6 electrode supported a high abundance of electroactive bacteria and enhanced their viability. With its simple fabrication, low weight, and exceptional electrochemical performance, the CNF/rGO-6 aerogel demonstrates significant potential as an electrode material for high-performance and cost-effective BES.
Oral leukoplakia (OLK) is a common and representative malignant disease of oral mucosa, and possess a higher risk of cancer. Compared with traditional surgical treatment, photodynamic therapy (PDT) has great potential in OLK treatment, due to its advantages of minimally invasiveness and low toxic side effects. However, traditional photosensitizer administration suffers from short retention time due to the fluid environment of saliva and extensive tongue movement, leading to poor drug (photosensitizer) utilization and limited therapeutic outcome. To address such issue, here a photosensitive guanosine (G)-based hydrogel system (G@GQD) was constructed, in which graphene quantum dots (GQDs) featuring high photosensitization activity was loaded through three dimensional (3D) fiber network physical encapsulation. The favorable adhesion of the G@GQD hydrogel on the tongue, together with sustained GQDs release, significantly enhanced the retention of GQDs within the oral cavity. As a result, G@GQD hydrogel could continuously generate high levels of reactive oxygen species (ROS) under irradiation, demonstrating a sustained therapeutic efficiency in vitro. Compared with free GQDs, G@GQD exhibited significantly improved PDT efficiency in treating 4-nitroquinoline 1-oxide (4-NQO)-induced OLK animals. This study presented a promising strategy in overcoming the drug retention barrier that caused by saliva and tongue movement, which has far-reaching significance for the future PDT therapies.
Light is a powerful tool for controlling hydrogel formation and drug release, which are essential in tissue engineering and drug delivery. Achieving orthogonal control over hydrogelation and drug release using different wavelengths of light offers precise spatiotemporal regulation but is challenged by limited penetration depth and spectral crosstalk of commonly used visible light. Herein, this work develops an orthogonal light-responsive hydrogel based on dual-wavelength upconversion nanoparticles (UCNPs) for controlled hydrogelation and drug release. Upon 808 nm excitation, these UCNPs emit green light, triggering the photopolymerization of hyaluronic acid-2-aminoethyl methacrylate hydrogels. While 980 nm induces ultraviolet emission, enabling controlled and sustained drug release. Through structural design, the emissions under dual-wavelength excitation exhibit no spectral crosstalk, enabling orthogonal light control of both processes. In vitro and in vivo experiments show that both hydrogel formation and drug release processes can be finely tuned by controlling the power density and excitation durations, significantly enhancing the spatiotemporal precision of drug delivery. This orthogonal light-responsive hydrogel holds significant potential for precise, spatiotemporally controlled drug delivery.
Induction of ferroptosis is a promising strategy for tumor treatment. In light of the fact that the inhibition of ferroptosis suppressor protein 1 (FSP1) can enhance the susceptibility of hepatoma cells to glutathione peroxidase 4 (GPX4) inhibitors, we hypothesized that FSP1 degraders may conspicuously improve the therapeutic efficacy of GPX4 inhibitors against hepatoma. Here, we developed a strategy using an iFSP1 analog (FSP1 inhibitor) and the pomalidomide (E3 ligase ligand) to construct proteolysis targeting chimeras (PROTACs) for degrading FSP1. Among these, C7, the first-in-class PROTAC degrader of FSP1, induced FSP1 degradation with a half-maximal degradation concentration (DC50) value of 0.66 µmol/L. The synergistic application of C7 (1 µmol/L) and the GPX4 inhibitor ML162 (100 nmol/L) markedly induced ferroptosis and effectively inhibited hepatoma cells viability. Further mechanism studies revealed that C7 targets FSP1 and down-regulates it through the ubiquitin-proteasome pathway. In vivo experiments demonstrated that the therapeutic alliance of C7 and ML162 markedly surpassed the efficacy of iFSP1 (FSP1 inhibitor) and ML162 in suppressing tumor proliferation. Collectively, these findings indicated that PROTAC degraders of FSP1 function as potent sensitizers of GPX4 inhibitors to induce ferroptosis, thus representing a promising strategy for hepatoma treatment.
Decellularized amniotic membrane (dAM) holds significant potential in tissue engineering; however, its inherent mechanical limitations and rapid degradation hinder its clinical translation. This study integrates dAM with high molecular weight polymer polycaprolactone (PCL) and natural gelatin (Gel) nanofibers using electrospinning technology and a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) covalent crosslinking system to produce two composite biomaterials. Both PCL-dAM and Gel-dAM composites demonstrate enhanced strain, tensile strength, and elasticity compared to pure dAM, showcasing improved mechanical properties and significantly reduced degradation rates, with Gel-dAM exhibiting superior overall performance. Gel-dAM also shows considerably better compatibility with fibroblasts, macrophages, and tendon stem cells than PCL-dAM, suggesting that it more effectively supports cell adhesion, proliferation, and differentiation, thus providing a more favorable microenvironment for tissue repair. In macrophage immune modulation, Gel-dAM significantly promotes the polarization of macrophages toward the M2 phenotype, exhibiting potential anti-inflammatory and repair-enhancing effects, thereby offering new insights into the use of dAM in tissue regeneration. These advancements open new possibilities for the clinical application of dAM, particularly in tissue repair and wound dressing.
Patchouli oil (PAO), a traditional herbal remedy with notable anti-inflammatory properties, has demonstrated significant therapeutic potential in gastrointestinal diseases. However, its instability in acidic environments and low bioavailability hinder PAO's clinical application. In this study, we developed a pharmaceutical solid-state form of PAO using a β-cyclodextrin (βCD)-based inclusion cocrystal technology, thus obtaining PAO-βCD cocrystals. PAO-βCD cocrystals exhibited enhanced dissolution and stability. We further encapsulated them in pH-sensitive Eudragit-coated pellets (PAO-βCD@pellet) to achieve site-specific delivery of PAO to the inflamed colon. In vivo results from the dextran sulfate sodium salt (DSS)-induced colitis mouse model showed that PAO-βCD@pellet significantly improved the colonic release of PAO, as evidenced by fluorescence tracking and quantitative analysis of patchouli alcohol, the main active compound of PAO. Furthermore, PAO-βCD@pellet demonstrated superior therapeutic efficacy, reducing disease activity index, preventing intestinal barrier damage, and modulating the gut microbiome. Histological examination confirmed alleviating intestinal epithelial cell damage caused by oxidative stress and inflammation. These findings suggest that PAO-βCD@pellet offers a promising targeted treatment strategy for inflammatory bowel disease (IBD) with enhanced stability, bioavailability, and therapeutic outcomes.
Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder with no effective therapeutic agents currently available. Inhibiting phosphodiesterase 4 (PDE4) has emerged as a promising strategy for AD treatment. In this study, we employed a synergistic approach combining generative recurrent neural network (RNN)-driven combinatorial compound design, virtual screening, and structure-activity relationship (SAR) analysis to discover novel PDE4 inhibitors. Utilizing α-mangostin as a hit compound (half maximal inhibitory concentration (IC50) = 1.31 µmol/L), we identified a novel PDE4 inhibitor, 13d (IC50 = 72.8 nmol/L) with moderate liver microsomal stability (rat liver microsomes (RLM), t1/2 = 32.4 min). In vitro activity results indicated that 13d exhibited favorable anti-inflammatory effects and promising neuroprotective activity. In vivo experiments demonstrated that 13d significantly improved AlCl3-induced zebrafish AD model by inhibiting PDE4 and reducing inflammatory cytokine. Further, 13d significantly alleviated AlCl3/d-galactose-induced AD mouse model. These findings highlight the potent PDE4 inhibitor 13d with promising anti-AD activity, underscoring the potential of artificial intelligence-driven drug discovery for novel therapeutic agents for AD.
Infected bone defects (IBD) are intricate and formidable conditions characterized by elevated rates of infection recurrence and delayed healing, resulting from dysregulation of the bone immune microenvironment (IME) mediated by microbes. The conventional approaches including surgical intervention and antibiotic therapy encounter challenges such as antibiotic resistance and susceptibility to postoperative infections. Considering the diverse impacts of various immune cells (ICs) and cytokines, the investigations into the IME have been conducted to offer potential strategies for treating IBD by addressing the requirements of infection eradication and bone regeneration (BREG). However, there is still a lack of review discussing the impacts of IME on IBD in light of its diverse components. Hydrogels, as promising materials in the treatment of IBD, can mimic the extracellular matrix of natural tissues, providing an optimal environment for cell growth and tissue regeneration. Recent studies have focused on investigating immune modulation through hydrogel delivery for treating IBD. This review aims to discuss the effects of different types of ICs and cytokines on the IME in IBD while summarizing current progress and strategies targeting this microenvironment using hydrogels. The insights gained from this review will aid the development of future immunomodulatory approaches for IBD treatment.
Tumor-associated carbohydrate antigen (TACA)-based cancer vaccines face clinical challenges due to heterogeneous TACA expression, which compromises antibody-mediated tumor recognition and leads to suboptimal therapeutic outcomes. To address this limitation, we report a combined strategy that integrates vaccination with TACA-based antibody-recruiting molecules. This approach simultaneously redirects anti-TACA antibodies to tumor cells expressing a secondary target, thereby enhancing the efficacy of TACA-based vaccines. Using sialyl-Tn (sTn) as a model TACA and epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) as model protein targets, we designed two nanobody (Nb)-sTn conjugates as TACA-based antibody-recruiting molecules: EGFR-targeting 7D12-sTn and HER2-targeting C7b-sTn. These conjugates were synthesized via sortase A-mediated ligation and demonstrated strong binding profiles. Importantly, they effectively redirected anti-sTn antibodies, generated by the Theratope vaccine, to target cells in situ, significantly improving the recognition of tumor cells by anti-sTn antibodies. The synergistic potential of these conjugates in amplifying the therapeutic effect of the sTn-KLH vaccine was further validated through complement-dependent cytotoxicity assays. This innovative strategy represents a highly promising approach to overcome the clinical challenges posed by TACA heterogeneity in cancer vaccine development.
The rapid proliferation of tumor cells is driven by metabolic reprogramming and redox regulation. Real-time monitoring of glutathione (GSH)/adenosine-5′-triphosphate (ATP) provides a dynamic perspective for tumor metabolism and is crucial for guiding precision treatment. We report a dual-site activatable fluorescent probe M901 for simultaneously detecting GSH and ATP without spectral overlap, and the detection range (GSH: 0–7 mmol/L, ATP: 0–6.5 mmol/L) matching the physiological concentration range. Based on this, M901 visualizes a bidirectional regulatory relationship between ATP synthesis↓ (energy imbalance) ↔ electron transport chain dysfunction ↔ reactive oxygen species (ROS)↑ ↔ GSH↓ (oxidative stress). Additionally, M901 reveals for the first time the dynamic compensatory mechanism between GSH and ATP in cellular oxidative stress induced by the inhibition of solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4). In vivo imaging further confirms oxidative stress and mitochondrial dysfunction are core pathological mechanisms leading to liver injury, with treatment efficacy positively correlated with GSH/ATP levels. Importantly, the dynamic visualization of GSH/ATP by M901 enables real-time evaluation of the anti-tumor effects of ferroptosis inducers and cisplatin, guiding successful precision resection of invasive malignant tumors (negative margins <0.2 mm). This study confirms the potential of M901 as a clinical visualization tool for diagnosing, treating and monitoring a variety of diseases.
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