Developing nanotherapeutics to circumvent intrinsic apoptosis resistance in cancer remains a key challenge in oncology. Cuproptosis, a non-apoptotic cell death modality, has emerged as a promising alternative, yet its therapeutic efficacy is frequently limited by robust intracellular antioxidant defense systems. Here, we developed an ultrasmall (ca.10 nm) mitochondria-targeted bimetallic nanozyme (RMOCZ) for synergistic ferroptosis-cuproptosis therapy against malignant melanoma. The Cu/Zn bimetallic core, functionalized with a chimeric mitochondrial targeting peptide, serves as both a pH-responsive copper reservoir and a dual-enzyme mimetic (peroxidase and glutathione oxidase). Upon endolysosomal acidification, RMOCZ disassembles to co-release copper ions and oridonin (ORI). The nanozyme oxidizes intracellular glutathione (GSH), a process significantly accelerated by co-delivered ORI. This disruption of redox homeostasis not only triggers ferroptosis by compromising cellular antioxidant capacity but also amplifies peroxidase-mediated reactive oxygen species (ROS) production, sensitizing tumor cells to copper-induced cytotoxicity. Concurrently, RMOCZ induces ferritinophagy to mobilize the endogenous labile iron pool and exacerbate lipid peroxidation. These events culminate in sustained copper-iron dual-ion overload. Following subsequent mitochondrial trafficking, the accumulated copper ions trigger canonical cuproptotic events, including the degradation of iron-sulfur (Fe-S) clusters and aberrant oligomerization of lipoylated DLAT. This irreversible mitochondrial dysfunction triggers potent immunogenic cell death (ICD) with robust damage-associated molecular patterns (DAMPs) release. In situ immunohistochemical analyses confirm that this RMOCZ-induced ICD profoundly remodels the immunosuppressive microenvironment, promoting CD86+ antigen-presenting cell maturation and enhancing intratumoral infiltration of CD3+ and CD8+ T cells. In vivo, RMOCZ demonstrates substantial melanoma regression with negligible systemic toxicity, providing a promising strategy for treating apoptosis-resistant refractory malignancies.

In this study, we aimed to design and synthesize a series of pentacyclic triterpenoids-triphenylphosphine (TPP) derivatives. A total of 22 derivatives were systematically synthesized and evaluated for their in vitro antibacterial activities against four pathogenic strains, namely, S. aureus, MRSA, E. coli, and P. aeruginosa, using the standard broth microdilution method. Notably, most derivatives demonstrated better antibacterial activity than the pentacyclic triterpenoids parent nucleus. Among them, Compound 1 performed the most potent antibacterial activity on MRSA (MIC = 0.78 μM), which was significantly better than norfloxacin, penicillin, tobramycin, and tetracycline at the same concentration. In addition, according to the results of hemolysis test, chick chorioallantoic membrane (CAM) assay, zebrafish toxicity test, and acute toxicity test, Compound 1 exhibited higher selectivity and biosafety. Finally, the mechanistic results suggested that Compound 1 may exert its antibacterial activity by acting on key targets such as SasG, IcaB, and MurQ, thereby affecting the biofilm formation process.

Wet granulation is a critical unit operation in the manufacturing of solid dosage forms. However, conventional wet granulation techniques are limited by significant batch-to-batch variability and scale-up challenges, making them difficult to meet the demands of continuous pharmaceutical manufacturing and robust quality control. As an emerging continuous granulation technology, Twin-Screw Wet Granulation (TSWG) has attracted extensive attention in pharmaceutical research and industrial applications due to its advantages of continuous processing, modular design, controllable mixing and shear, and reduced scale-up effects. This review systematically summarizes and critically evaluates the core technologies and underlying mechanisms of TSWG, including equipment configuration, screw design, and granulation mechanisms. The relationships between formulation variables, equipment parameters, and process conditions with critical quality attributes (CQAs) of granules, such as particle size distribution, porosity, and mechanical strength, are comprehensively analyzed. Furthermore, the application of Process Analytical Technology (PAT) for real-time monitoring is discussed, together with recent advances in process modeling and optimization using Discrete Element Method-Computational Fluid Dynamics (DEM-CFD) coupled models, Population Balance Models (PBMs), Machine Learning (ML), and Artificial Intelligence (AI). The potential of integrating AI with PAT, machine vision, and data-driven models for granule quality prediction, online monitoring, and intelligent process control is also highlighted. Finally, the current challenges of TSWG are addressed, including process scale-up consistency, adaptation to raw material batch variability, and control of active pharmaceutical ingredient (API) polymorphic stability. Future development is expected to rely on interdisciplinary integration to advance technological innovation and support Quality by Design (QbD) paradigm in pharmaceutical manufacturing.

Real-time monitoring of continuous powder blending, particularly in the case of botanical drugs containing cohesive natural product powders, remains a considerable challenge due to limitations in spectral data quality and model robustness. In this paper, an integrated strategy that combines a sampling interface design with chemometrics optimization was employed to develop a robust online near-infrared (NIR) spectroscopy for monitoring the continuous blending of a quaternary botanical drug formulation with low concentration of active pharmaceutical ingredient (API) (i.e. the paeonol at 0.33-3.0% w/w). The inclined chute interface was designed to reduce its cross-sectional area, thereby stabilizing powder flow, increasing the sample mass at the NIR probe, and improving spectral data quality by minimizing baseline drift and noise. The Gaussian smoothing in conjunction with standard normal variate (SNV) transformation was identified as the optimal spectral preprocessing procedure. Seven variable selection algorithms were compared, and the successive projections algorithm (SPA) yielded the most effective and interpretable wavelengths that were consistent with the characteristic absorption bands of the paeonol. The optimal PLS model based on the data collected from the improved interface exhibited superior predictive performance compared with the model built from the initial sampling interface, achieving the validation R2 of 0.9858 (vs. 0.9529) and ratio of performance to deviation (RPD) of 7.26 (vs. 5.51). The uncertainty profile showed the uncertainty limits were all within acceptable limits of ±20% at each studied concentration, verifying the accuracy and reliability of the established NIR method. In conclusion, this work established a comprehensive framework that addressed both the physical aspects of process sampling and the chemometric modeling strategies to enable accurate, real-time monitoring of challenging cohesive powder blends in continuous pharmaceutical manufacturing.

Background Breast cancer remains a critical unmet clinical challenge due to its aggressive metastasis behavior and limited treatment options. Topoisomerase inhibitors are widely available clinically but fail to address the compensatory upregulation of alternative isoforms in metastatic breast cancer. Techonology We engineered redox-responsive, carrier-free nanoassemblies (POD-2S-CPT NPs, PSC NPs) by co-assembling camptothecin (CPT, Topo I inhibitor) and podophyllotoxin (POD, Topo II inhibitor) linked via a disulfide bond. This design achieved high drug loading and leveraged the tumor microenvironment (TME), specifically elevated glutathione (GSH), for targeted drug release and maximized the synergistic therapeutic effect of Topo I/II inhibition. Results The PSC NPs demonstrated GSH-responsive drug release and selective cytotoxicity against MCF-7 cells. Mechanistically, they induced necroptosis via concurrent nuclear Topo I/II inhibition, mitigating compensatory resistance. In vivo, PSC NPs exhibited potent antitumor efficacy and significantly suppressed lung metastasis, without significant systemic toxicity. RNA-seq analysis revealed concurrent downregulation of the CXCL1/5-S100A8/9 axis in treated tumors, suggesting potential immunomodulatory effects alongside direct DNA damage. This self-assembled, redox-responsive nanoplatform enabled synergistic dual Topo I/II inhibition within the TME. It demonstrated potent anti-tumor and anti-metastatic activity with a favorable safety profile, presenting a promising potential strategy for metastatic breast cancer therapy.

Drug repurposing (DR) offers an efficient and cost-effective strategy for pharmaceutical development by identifying new therapeutic applications for existing drugs. The effectiveness of this approach relies on accurately uncovering potential drug-disease associations; however, capturing the complex biological interactions underlying these associations remains a major challenge. Current computational approaches frequently overlook the critical regulatory role of the microbiota in modulating drug action pathways. Moreover, many methods fail to preserve semantic consistency during multimodal biological data integration and heterogeneous graph augmentation, thereby limiting their representational capacity. To overcome these limitations, we propose DVMMHGNN, a heterogeneous graph contrastive learning framework for microbe informed drug repurposing that jointly integrates structural and meta-path information. First, a multimodal feature fusion module embeds heterogeneous biological entities into a unified latent space to ensure cross-modal feature alignment. Second, a graph-masked autoencoder is employed to capture high-order representations from similarity networks. Finally, DVMMHGNN enhances semantic coherence through contrastive learning at both the structural and meta-path levels, aligning embeddings across multiple views to effectively capture both local and global semantics. Experimental evaluations on the constructed benchmark data set demonstrate that DVMMHGNN consistently outperforms nine state-of-the-art methods in predicting drug-disease associations, achieving superior performance across AUC, AUPR, and F1-score metrics. Ablation studies further validate the contribution of each model component, while case analyses highlight the potential of DVMMHGNN to identify novel drug indications and guide therapeutic strategy development.

Oral administration of insulin (INS) could be absorbed into systemic circulation only if the carrier protected it from the hostile gastrointestinal conditions. However, traditional macromolecular carriers have not totally overcome challenges in addressing these biological barriers. In this study, inspired by small molecule natural products (SMNPs), we demonstrate the multi-functional self-assembly nanoparticles (BA-Al NPs) originating from baicalin (BA) and AlCl3 through coordination bonds and hydrogen bonds. As a novel carrier for oral insulin delivery (INS@BA-Al NPs), it displayed effective capacity in pH stimuli-responsive insulin release, intestinal mucoadhesion and transepithelial absorption enhance. Meanwhile, BA improved the paracellular permeability for insulin absorption, because of its downregulation at both mRNA and protein level on internal tight junction proteins. In vivo experiments exhibited remarkable bioavailability of INS and an ideal glucose homeostasis in the type I diabetic rat model. This study offers a novel frontier of multi-functional carriers based on SMNPs with self-assembly character and bioactivity, which could be a promising strategy for diabetes therapy.

ETHNOPHARMACOLOGICAL RELEVANCE:Microbial fermentation is an indispensable processing technology in traditional Chinese medicine (TCM). This technology uses functional microorganisms to transform bioactive components, addressing limitations of TCMs including low solubility of active ingredients, poor bioavailability and potential toxicity. Microbial fermentation preserves TCM's traditional therapeutic effects, integrates modern advantages, and thus bridges traditional TCM knowledge with current healthcare needs. However, inconsistent fermentation outcomes due to strain specificity, potential microbial contamination during scaling, and uncharacterized long-term safety of novel fermented metabolites remain non-negligible risks that require targeted mitigation. AIM OF THE REVIEW:Despite the increasing attention on microbial fermentation in TCM, existing reviews primarily focus on phenomenological descriptions (e.g., component content changes, basic fermentation effects) and lack systematic integration of molecular mechanisms, emerging fermentation strategies, and industrial application guidance, and differentiation of evidence types (in-vitro, in-vivo, human). Notably, the interaction mechanisms between microorganisms and TCM components, as well as standardized processes for fermentation scalability, remain underexplored. To address these gaps, this review updates the latest progress in microbial application in TCM, with a focus on enzyme-mediated component transformation mechanisms, structure-activity relationships of key bioactive substances (polysaccharides, flavonoids, alkaloids), optimization of fermentation processes (strains, methods, parameters), and practical applications in health food, animal husbandry, and medicine. It aims to synthesize scattered research evidence into a cohesive theoretical framework, clarify current technical bottlenecks, and provide targeted references for subsequent mechanistic exploration and industrial translation of fermented TCM. MATERIALS AND METHODS:Information relevant to the Application of Microorganisms in Fermented TCM was collected by searching the scientific databases (Google Scholar, PubMed and International Plant name Index). Botanical plant names were validated using the Plant List (www.theplantlist.org). To ensure the rigor and objectivity of this review, we established explicit inclusion and exclusion criteria for literature screening. INCLUSION CRITERIA:(1) Original research or reviews published in peer-reviewed journals; (2) Studies focusing on microbial fermentation of TCM (including single herbs, compound formulas, and TCM-derived resources); (3) Research involving clear fermentation strains, process parameters, or component-efficacy relationships; (4) Studies providing quantitative data on component changes or pharmacological effects. EXCLUSION CRITERIA:(1) Conference abstracts, unpublished dissertations, or non-peer-reviewed literature; (2) Studies with unclear experimental design or incomplete data; (3) Duplicate publications or secondary analyses of existing datasets; (4) Research unrelated to microbial fermentation (e.g., chemical synthesis or physical processing of TCM). Literature screening was performed by two independent researchers, and eligible studies were cross-validated to ensure reliability. RESULTS:Functional microorganisms drive transformations of TCM components during fermentation. They decompose macromolecules into absorbable small molecules, convert toxic components into low-toxic derivatives, and generate new bioactive compounds. In-vitro studies confirm these component transformations; in-vivo animal models validate enhanced efficacy and reduced toxicity; and preliminary human evidence supports potential clinical applications. These changes enhance TCM efficacy and improve safety. Fermented TCM shows broad application value in health food and medicine. However, microbe-TCM interaction mechanisms remain unclear, standardization is insufficient and microbial resources are underexplored. CONCLUSIONS:Microbial fermentation optimizes TCM quality by enhancing efficacy, reducing toxicity and expanding applications, with a clear link between component changes and improved pharmacology. Future research should use multi-omics to clarify interactions, establish standardized processes and explore novel microbial resources.

Flavor profile and water dissolvability serve as core evaluation benchmarks for the quality of food and medicinal plant-derived instant granules. Currently, studies integrating flavor and dissolvability analysis to comprehensively characterize the overall performance of such granules remain scarce, and the existing literature lacks systematic comparative research on commercial products across multiple sources and batches. This study investigated 90 batches of four categories of plant extract instant granules and established a dynamic-static joint evaluation system coupled with multiple indicators and the Analytic Hierarchy Process (AHP). The three primary indicators were dissolving extent, dissolving rate, and taste, with equal weights assigned to each; the secondary indicators were classified and integrated based on the results of Principal Component Analysis (PCA) and correlation matrix. Quantitative analysis revealed that the comprehensive evaluation scores of all 90 batches of samples fluctuated between 0.5406 and 0.9503, and obvious disparities existed among different granule varieties. This multi-index evaluation framework effectively avoids the subjective bias inherent in conventional evaluation approaches, and lays a solid scientific foundation for quality supervision, formula optimization research and development, as well as market popularization of plant-based instant granules.

Background: Twin-screw wet granulation (TSWG) is a promising continuous manufacturing technology, featuring high operational flexibility, short residence time and consistent quality. The process development of TSWG relies on the synergy of material characterization, screw configuration, and process parameter optimization. Objective: In order to fully combine various design variables, and to accelerate the process development of TSWG, a material–process–equipment integrated design (MPEID) methodology is first applied to the TSWG process of Guizhi Fuling capsule, a botanical drug product. Methods: First, an equivalent formulation was designed to save trial costs. Second, 3D printing technology was used to customize both conveying and kneading elements with the lead, with the kneading discs stagger angle (SA) and the thickness (thick) as screw element variables. The position of fabricated kneading elements was varied to generate different screw configurations. Then, the critical screw parameters (CSPs) and critical process parameters (CPPs) were identified by a two-step design of experiment (DOE) toward optimizing granule quality. Results: As a result, the SA and thick were identified as CSPs, and the liquid-to-solid ratio was the CPP. Under the optimal TSWG process conditions, the twin-screw granulator could be operated under low torque (i.e., average torque = 1.48 ± 0.06 Nm). The dried granules exhibited superior flowability, as well as highly consistent particle size distribution with industrial batches. After capsule filling, the dissolution test results showed the prepared Guizhi Fuling capsules reached 93.7% cumulative dissolution at 15 min, which approached that of commercial capsules (i.e., 93.0%). Conclusions: This study demonstrated the feasibility of proposed MPEID methodology, supporting the efficient and cost-effective process development of TSWG.

Instrumental Analysis is a mandatory course for various majors in medical and pharmaceutical universities across China. The teaching of the Mass Spectrometry (MS) chapter occupies an extremely important position in this course. Mass spectrometers are typically modern, high-end scientific instruments. Their core technologies are not only a bridge connecting basic disciplines such as physics and chemistry with a series of subsequent medical and pharmaceutical specialty courses but also powerful tools for students to engage in scientific research in the future. "New Medicine" represents the rejuvenation and establishment of medical specialties in Chinese higher education in response to the new demands brought about by the scientific and technological revolution and industrial evolution. This initiative aims to promote innovation in medical education frameworks and the cultivation of talents with interdisciplinary expertise. To adapt to the "New Medicine" era, we analyzed and identified the previous challenges in the Instrumental Analysis course at Beijing University of Chinese Medicine (BUCM) and conducted teaching improvements using the MS chapter as an example. This paper provides an overview of advancements made to the redesigned MS teaching, encompassing the educational philosophy of "One Core with Three Characteristics", upgraded teaching objectives, updated teaching content, enriched teaching approaches, and so on. This can serve as an example for the improvement of teaching in other chapters of the Instrumental Analysis course. It can also provide insights into the theoretical foundation of the "New Medicine" initiative from the perspective of strengthening the teaching of basic courses in traditional Chinese medicine (TCM) colleges and universities.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, neuroinflammation, and oxidative stress. However, current therapies remain largely symptomatic. Traditional Chinese Medicine (TCM)-derived monomers exhibit considerable anti-AD potential owing to their multitarget neuroprotective activities. However, their therapeutic translation is severely limited by poor stability, low bioavailability, and restricted brain delivery across the blood-brain barrier (BBB). This review summarizes the pathological basis of AD, the neuroprotective mechanisms of representative TCM-derived monomers, and the major BBB-related barriers that hinder effective brain delivery. Particular emphasis is placed on lipid-based nanocarriers, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), as platforms for improving drug stability, BBB transport, and brain accumulation. We further highlight innovative delivery strategies that integrate ligand-mediated targeting with biomimetic modification, particularly cell membrane camouflage and exosome-inspired engineering. These approaches may confer immune evasion, prolonged circulation, enhanced biocompatibility, and improved lesion-oriented delivery. Finally, we discuss the challenges facing the clinical translation of lipid-based nanocarriers, including large-scale production, quality control, regulatory considerations, and long-term safety. Collectively, these lipid-based nanoplatforms provide a promising framework for advancing next-generation nano-TCM therapeutics for AD. Future progress will depend on optimized carrier design, rigorous mechanistic validation, comprehensive long-term safety assessment, and clinically relevant translational studies.

Ethnopharmacological relevance Acute myocardial infarction (AMI) significantly increases the global health and economic burden. Although Western drug therapies have successfully reduced mortality in patients with acute myocardial injury, they are not without drawbacks, including a range of adverse effects. Although Rhizoma Corydalis (YHS) has been used in China for over a thousand years to prevent cardiac conditions, its precise preventive and therapeutic effects on AMI areremain unclear, necessitating further research into its mechanisms of action. Aim of the study To assess the therapeutic potential of YHS against AMI, this study seeks to identify its active components and thereby establish its pharmacological basis. Materials and methods In this study, an AMI model was established in mice by tail vein injection of doxorubicin (DOX). Network pharmacology and UHPLC-Q Exactive Orbitrap HRMS technology were used to predict the active constituents, target molecules, and mechanisms of action of YHS against AMI. Echocardiography, histopathological examination, and serum biochemical assays were utilized to assess the therapeutic benefits of YHS and its main active component TP on the AMI mice model. The effects of YHS on the signaling pathways and gene expression profile in AMI were investigated by transcriptome analysis. ROS staining, Western blotting, PCR, and immunofluorescence were utilized to validate the mechanisms of YHS in preventing AMI. Results According to our research, DOX-induced changes in body weight and cardiac indices were considerably improved by both YHS and its main active component TP, which also successfully decreased levels of lactate dehydrogenase (LDH) and creatine kinase MB isoenzyme (CK-MB). YHS and TP significantly improved the low EF and FS levels brought on by DOX overdose, according to echocardiography. Myofibrillar disarray, myocardial cell nuclear atrophy, and inflammatory cell infiltration in the heart were all improved by YHS and TP, according to histological study. The NOD-like receptor pathway, which included important proteins like Nox2, TXNIP, NLRP3, and Caspase-1, may be the basis for YHS's ACT-improving mechanism, according to network pharmacology prediction and transcriptomics research. In addition, DHE staining, immunofluorescence detection, PCR, and Western blot experiments demonstrated that YHS improved AMI in mice by inhibiting DOX-activated Nox2, lowering excessive ROS production, suppressing TXNIP translocation, and reducing inflammasome expression (including NLRP3 and Caspase-1). Conclusion According to research, YHS successfully reduced doxorubicin-induced acute myocardial injury by blocking the NOD-like receptor pathway, lowering levels of reactive oxygen species (ROS) and the important oxidative stress gene Cybb, and decreasing the production of inflammasomes. This work offered fresh perspectives on the pharmacological activities of traditional Chinese medicine in treating AMI from a variety of angles by first revealing the intricate processes by which YHS prevented AMI at the levels of oxidative stress and inflammasome.

Ethnopharmacological relevance : Plants used in traditional medicine have long provided valuable clues for drug discovery, yet systematically connecting their documented therapeutic effects with modern understanding of biological mechanisms remains a key scientific question. Bridging the gap between traditional knowledge, clinical symptom profiles, and contemporary molecular-level regulation is essential for advancing the study of herbal medicine. Objectives This study aims to develop a multimodal graph attention learning framework, named MAGED, which integrates knowledge graphs with gene expression dynamics to improve the accuracy and interpretability of Herb-Target Interaction (HTI) prediction. Methods MAGED incorporates multi-source heterogeneous data, including traditional Chinese medicine (TCM) properties, hierarchical clinical symptom information, and molecular-level biological data, such as gene expression dynamics under drug intervention and causal biological networks. A multimodal fusion encoder is employed to embed herb attributes into efficacy-related feature vectors, which are then combined with functional representations (e.g., normalized enrichment scores) to form a unified contextualized representation. Additionally, a hierarchical graph attention network is designed to integrate macroscopic symptom-gene associations with microscopic regulatory pathways, thereby establishing a coherent inference chain from herbal effects to biological targets and phenotypic symptoms. Results Systematic experimental evaluations demonstrated that MAGED significantly outperforms existing baseline methods across multiple evaluation metrics, achieving a 59.8% improvement in HR@10. The model also exhibited superior ranking and recall performance under cold-start scenarios. In a case study on Scutellaria baicalensis, 8 out of the top 10 predicted targets were supported by existing literature, with functional or direct interaction evidence, and some targets were further validated through molecular docking. Conclusion MAGED provides an accurate and interpretable framework for predicting herb-target interactions, effectively integrating traditional knowledge with modern molecular evidence. This approach shows strong potential to facilitate the discovery of herbal mechanisms and the identification of novel therapeutic targets.

The severe inflammation associated with infectious or inflammatory diseases significantly contributes to mortality. Interferon regulatory factor 3 (IRF3) represents a potential anti-inflammatory target, but the development of IRF3 inhibitors has not yielded satisfactory results to date. In this study, we established a phenotype-based high-throughput screening system to conduct activity-guided hierarchical screening of clinical frequently used anti-inflammatory and anti-rheumatic herbal extracts and compounds. Employing a Gaussia-luciferase reporter system driven by the IFNB1 promoter, we identified sinomenine as a potent type I interferon (IFN) inhibitor from a set of 28 anti-inflammatory herbal products. Furthermore, among 24 synthesized sinomenine derivatives modified by various electrophilic groups, Sim-9 (2.5–10 μM) dose-dependently inhibited IFN responses triggered by TLRs, RLRs, and STING activation in mouse RAW264.7 cells and in human THP-1 cells, HT-29 cells and A549 cells. We demonstrated that Sim-9, by covalently binding to Cys222, induced a conformational change in the pLxIS motif-binding surface of IRF3, thus blocking its interaction with upstream adapters, including TRIF, MAVS and STING, and subsequent homodimerization of IRF3 itself, which were all essential for activation of type I IFN responses. In in vivo experiments, we showed that injection of Sim-9 (30, 60 mg/kg, i.p.) effectively protected against devastating inflammation in cecal ligation and puncture (CLP)-induced sepsis in mice, and improved cerulein-induced pancreatitis by inhibiting IRF3. Our study discovers Sim-9 as a novel covalent allosteric inhibitor of IRF3 and reveals that the pLxIS motif binding surface represents a previously uncharacterized druggable target for IRF3 activation, providing a promising therapeutic strategy for the treatment of severe inflammatory injuries.

Liver fibrosis remains a critical unmet medical challenge, where glucocorticoids’ therapeutic potential is constrained by systemic toxicity. We innovatively address this through an amphiphilic prodrug (DEI) engineered by Michael addition-conjugating dexamethasone with I-C-F-6, which self-assembles into γ-glutamyltranspeptidase (GGT)-responsive nanoparticles for liver-targeted delivery. This nanoplatform achieves spatial precision through enzyme-triggered drug self-immolative release exclusively in fibrotic livers, minimizes systemic toxicity, and modulates fibrosis pathogenesis via dual pathways. DEI-NPs could suppress hepatic stellate cell activation via TGF-β/Smad3 and TH17 pathway blockade to halt collagen I/IV deposition, and reprogram intrahepatic immunity through retinol metabolism-mediated TH17/Treg rebalancing (Cyp2a1↓/STAT1↑). Our work pioneers a paradigm-shifting strategy in glucocorticoid therapy that merges GGT-activated spatial control with immunometabolic reprogramming, effectively overcoming critical bottlenecks in fibrosis therapy.

Activation of autophagy represents a critical pathway for eliminating activated hepatic stellate cells (HSCs). However, excessive autophagy induction may trigger ferroptosis, thereby aggravating liver damage. This study proposes synergistic regulation of HSC autophagy and ferroptosis as a novel strategy against liver fibrosis. We engineered an injectable Zn2+-coordination supramolecular hydrogel (termed ASA-Gel) through self-assembly of natural bioactive compounds artesunate (ASA) and glycyrrhizic acid (GA) without exogenous carriers. What’s more, Zn2+ in ASA Gel could significantly reduce the concentration of hydrogel. Molecular dynamics simulations reveal that ASA Gel formation is primarily governed by Zn2+-carboxylate coordination bonds and intermolecular hydrogen bonding. In CCl4-induced fibrotic mice, ASA Gel showed superior efficacy to ASA monotherapy and GA-Zn2+ complexes. Molecular profiling revealed that ASA Gel upregulated Atg9A and Atg101 in the liver, thereby promoting autophagosome formation, inhibiting P62 expression, and enhancing autophagic flux. Moreover, ASA Gel significantly promoted the expression of GPX4 and SLC7A11 genes, indicating that it inhibited the ferroptosis process in liver tissue. This work establishes a carrier-free hydrogel platform for spatiotemporally coordinated regulation of autophagy and ferroptosis in HSCs.

Qingfei Decoction (QFD) is recognized as one of the 100 classic prescriptions by the National Administration of Traditional Chinese Medicine of China and is widely used for the treatment of pulmonary diseases. Chronic obstructive pulmonary disease (COPD) is a common respiratory condition primarily characterized by airway obstruction. It’s necessary to examine the therapeutic effect of QFD in the treatment of COPD and elucidate its potential effective components, targets, and pathways. This study utilized UHPLC coupled with HRMS to identify the chemical constituents of QFD, resulting in the qualitative analysis of 68 compounds. Network pharmacology predicted 30 gene targets, including IL6, AKT1, and EGFR, and revealed 45 compounds, including ruscogenin, schisandrin A, and esculetin that may contribute to its therapeutic effects on COPD. Subsequently, an elastase-induced COPD mouse model was employed to evaluate the efficacy of QFD. The effects of QFD were assessed through hematoxylin and eosin (H&E) staining, periodic acid-Schiff (PAS) staining, and real-time quantitative polymerase chain reaction (RT-qPCR) on lung tissues. Transcriptomic analysis indicating QFD treatment of COPD primarily acted on the IL-17 signaling pathway, which was consistent with the network pharmacology results. Furthermore, RT-qPCR, immunofluorescence, and western blot demonstrated reduced mRNA and protein expression levels of TRAF3IP2, TRAF6, IL17, and TNFα. These findings confirmed that QFD effectively reduced inflammation, likely by down-regulating the IL-17 signaling pathway, thereby treating COPD.

Background/Objectives: Tablet is the most popular oral solid dosage form, and high-shear wet granulation and tableting (HSWGT) is a versatile technique for manufacturing tablets. The conventional pharmaceutical development for HSWGT is carried out in a step-by-step mode, which is inefficient and may result in local optimal solutions. Inspired by the co-design philosophy, a formulation–process–product integrated design (FPPID) framework is innovatively brought forward to enable the target-oriented and simultaneous exploration of the formulation design space and the process design space. Methods: A combination of strategies, such as a material library, model-driven design (MDD), and simulation-supported solution generation, are used to manage the complexity of the multi-step development processes of HSWGT. The process model was developed at the intermediate level by incorporating dimensionless parameters from the wet granulation regime map approach into the process of the partial least square (PLS) model. The tablets tensile strength (TS) and solid fraction (SF) could be predicted from the starting materials’ properties and process parameters. The material library was used to diversify the model input and improve the model’s generalization ability. Furtherly, the mixture properties calculation model and the process model were interconnected. Results: A four-step FPPID methodology including the target definition, the formulation simulation, the process simulation, and the solution generation was implemented. The performance of FPPID was demonstrated through the efficient development of high-drug-loading tablets. Conclusions: As a holistic design method, the proposed FPPID offers great opportunity for designers to handle the complex interplay in the sequential development stages, facilitate instant decisions, and accelerate product development.