With the increasing frequency of high-altitude travel,mountain-eering,military deployment,and occupational exposure to extreme environments,hypobaric hypoxia-induced acute lung injury and high-altitude pulmonary edema(HAPE)have emerged as significant medical challenges1.These disorders are charac-terized by abrupt onset,rapid progression,and marked interindi-vidual susceptibility2.
Featured with irregular,leaky,and distorted structures,abnormal tumor vasculature not only meets the metabolic demands of tumor growth and metastasis,such as the supply of oxygen and nutrients,but also fosters an immunosuppressive microenvironment1.This compromised vascular state undermines the effectiveness of im-munotherapies such as programmed cell death ligand 1(PD-L1)blockade.
K-RAS mutations are among the most prevailing oncogenic drivers in human cancers,yet they have long been considered"undruggable"due to the absence of deep hydrophobic pockets on the protein surface and the high affinity of RAS for GTP.
Microorganisms reside throughout the human body,including the skin,oral cavity,and gastrointestinal tract.Advances in next-generation sequencing have provided unprecedented insights into microbial communities and their associations with human health and disease.
Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a median survival of 3-5 years after diagnosis1,exhibiting particularly high incidence and mortality rates in Europe and North America2.Its pathological mechanisms involve epithelial cell activation,recurrent lung tissue injury,and impaired repair,leading to fibroblast activation,excessive transforming growth factor β(TGF-β)secretion,and extracellular matrix(ECM)accumulation,thereby impairing alveolar gas exchange3.
Intratumoral bacteria, especially Gram-positive bacteria (G+), have a unique bacterial niche in breast cancer that promoted tumor progression. However, the effects of G+ have so far been overlooked, serving an “invisible driver” of breast cancer. Moreover, due to the altered biological structure of G+ in tumor cells and the penetration barrier of antibiotics, the effect of antibiotic-mediated eradication of G+ in tumors is limited. Here, to simultaneously inhibit intratumoral G+ and tumor cells via ferroptosis therapy, an amorphous nano-assembly (DFTV) was constructed by assembling doxorubicin (DOX), tannic acid (TA), FeSO4, and vancomycin (Van). DFTV treatment effectively targets intratumoral G+, thereby inhibiting the growth of the breast tumor and postoperative recurrence by downregulating the expression of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Moreover, inhibiting intracellular G+ also restrains the reorganization of F-actin to form pseudopodia, thereby impairing tumor cell motility and blocking metastasis. Collectively, DFTV improves the antitumor efficacy by targeting G+ in breast tumors, offering novel insights into overcoming the limitations associated with the lack of intratumoral antibacterial therapy in clinical breast cancer treatment protocols.
Prodrug nanoassemblies offer an innovative approach to drug delivery, but their lysosomal entrapment often impairs drug release. Notably, tertiary amine structures can undergo protonation reactions, thereby facilitating lysosomal escape through the proton sponge effect. In this study, we developed three novel paclitaxel prodrug nanoassemblies (PTX-SS-NO NPs, PTX-SS-CC NPs and PTX-SS-NC NPs) featuring distinct heterocyclic tertiary amine structures to investigate structure-activity relationships in lysosomal escape and drug delivery. Among them, PTX-SS-NC NPs demonstrated excellent lysosomal escape capability, enabling rapid drug release into the cytosol. Systematic evaluation revealed that the PTX-SS-NC NPs exhibited optimized pharmacokinetics and significant tumor accumulation, further contributing to their strong antitumor efficacy. Our findings establish heterocyclic tertiary amines as crucial design elements for overcoming lysosomal entrapment and optimizing chemotherapeutic prodrug nanoassemblies.
The liver and pancreas are metabolically intertwined organs whose bidirectional communication is critical for maintaining systemic homeostasis. Dysregulation of this inter-organ crosstalk is a central driver in the pathology of a growing list of prevalent diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), liver cancer, acute and chronic pancreatitis, and various forms of diabetes. Given the substantial global health burden of these conditions and the lack of effective, Food and Drug Administration (FDA)-approved pharmacological interventions for those diseases, understanding the intricate mechanisms is an urgent and timely endeavor. This review provides a comprehensive synthesis of recent advancements in deciphering the molecular basis of liver-pancreas communication. We explore the multifaceted signaling networks involved, including the roles of liver-derived hepatokines, pancreas-derived hormones, extracellular vesicles, and metabolic exchanges. This axis is further integrated within broader systemic networks involving the gut, neuronal system, adipose tissue, and skeletal muscle. While clinical trials targeting this communication show promise (e.g., FGF21- and bile acid-related drugs), significant challenges remain, particularly the lack of FDA-approved pharmacological treatments for alcohol-associated liver disease (ALD), and acute/chronic pancreatitis. Future research must elucidate specific signaling pathways, identify novel pancreas-derived factors, and develop innovative therapeutic strategies. In particular, small molecule drug discovery based on polypharmacology, for these complex metabolic and organ-specific diseases.
To the Editor: The glucagon-like peptide-1 receptor(GLP-1R)plays a central role in glucose homeostasis and energy balance through its acti-vation by the incretin hormone GLP-11.It is highly expressed in pancreatic islets and the gastrointestinal tract,and is also present in the brain and heart2.At the signaling level,GLP-1R primarily couples to Gs,activating adenylate cyclase,elevating intracellular cyclic AMP(cAMP),and stimulating PKA/EPAC pathways3.
Glioblastoma (GBM), the most aggressive primary brain tumor, remains a formidable therapeutic challenge, with a median survival under 15 months. Despite the current standard of care-comprising maximal safe surgical resection, radiotherapy, and temozolomide chemotherapy-patient outcomes have seen minimal improvement over the past two decades. A key barrier to effective treatment is GBM’s robust and multifaceted immunosuppressive network, which critically undermines antitumor immunity. While much of the research has focused on the local immunosuppressive tumor microenvironment, systemic immunosuppression represents an equally important yet often underappreciated obstacle, significantly impairing host immune competence. Effective immunotherapy relies on an intact and functional immune system capable of mounting durable T cell-mediated responses. However, GBM induces profound systemic immune dysfunction, manifested by severe lymphopenia and depletion of effector immune cells, which further limits immune-mediated tumor control. Therefore, a comprehensive understanding of both systemic and local immunosuppressive mechanisms is essential for the rational design of effective immunotherapeutic strategies. In this review, we examine the unique physiological features of the brain, dissect the immunosuppressive landscape of GBM at both local and systemic levels, and highlight recent insights into the underlying mechanisms. We also discuss current immunotherapeutic modalities, and emerging drug delivery strategies aimed at overcoming immunosuppression to improve therapeutic efficacy.
To the Editor: Esophageal cancer,the seventh most lethal cancer in the world,is divided into two pathologically distinct subtypes:esophageal squamous cell carcinoma(ESCC;accounts for over 90％)and esophageal adenocarcinoma,which differ significantly in risk and geographic factors1,2.
Membrane-derived biomimetic nanovesicles have emerged as a promising platform in cancer immunotherapy due to their intrinsic biocompatibility, functional plasticity, and capability to modulate immune responses. By integrating various immunotherapeutic agents, including immune checkpoint inhibitors, tumor antigens, and immunostimulatory adjuvants, these vesicles can be engineered to mimic natural immune communication and overcome key barriers in the tumor immune microenvironment. This review summarizes recent advances in the design, functionalization, and application of biomimetic nanovesicles for anti-tumor immunity. We particularly highlight strategies that harness these vesicles to enhance innate and adaptive immune responses, reverse immune suppression, and synergize with existing immunotherapy modalities. Furthermore, we discuss the challenges associated with biosafety, large-scale manufacturing, and clinical translation. Continued innovation in vesicle engineering and immunological modulation will be crucial for transforming biomimetic nanovesicles into viable next-generation cancer immunotherapeutics.
Abnormal tumor vasculature greatly accelerates tumor progression and diminishes antitumor treatments. Restoring perivascular NO gradients is available to maintain tumor vessel homeostasis and promote tumor vascular normalization. However, exogenously delivering NO strategies lacks the durability to maintain precise NO localization around tumor vessels. Herein, we design a lipid nano delivery system (MC@L) and exploit endothelial transcytosis to deliver metformin (Met) and CaO2 into tumor vascular endothelial cells (ECs) and tumor cells for achieving tumor vascular normalization-boosted antitumor immunotherapies. The Ca2+ and Met released in ECs could restore perivascular localization of NO by activating endothelial NOS (eNOS). Additionally, MC@L internalized by tumor cells could cause CaO2-induced immunogenic cell death (ICD), together with hypoxia relief and acid neutralization mediated by O2 generation and H+ consumption during CaO2 degradation, thus further improving the immune effector cell functions under the accompaniment of Met-mediated inhibition of tryptophane uptake in tumor cells. Such a lipid nano delivery system greatly increases the susceptibility of 4T1 tumor-bearing mice to PD-L1 blockade efficacy.
Bacterial extracellular vesicles (BEVs) secreted by bacteria are considered as messengers for the crosstalk between gut microbiota and wounded skin via the "gut-skin axis". The BEVs with the lipid bilayer nanostructures can deliver various bioactive molecules from their parent bacteria to the host cells, modulating the signal pathways related to wound repair and regeneration. Besides, the cutting-edge gene editing strategies and mature bacterial culture methods further endowed their more customizable and scalable manufacture compared to the most commonly used extracellular vesicles from mammalian cells. Therefore, more and more BEVs have been exploited directly as bioactive nanocarriers or engineered as delivery vehicles for wound treatment. Herein, the present review began with an overview of the gut-skin axis to better comprehend the bioactivates of BEVs towards wound healing. Their biogenesis, isolation, and uptake were then introduced. A summary of recent advancements in exploring BEVs for accelerated wound healing was followed, with a focus on their roles as nanocarriers for delivery. Diverse engineering approaches to functionalize BEVs were especially discussed for optimal wound management. Constructive insights regarding the new upsurge of BEVs for wound treatment were provided in the end to boost these innovative therapeutic modalities from bench to bedside.
Vascular calcification(VC)is a major cause of cardiovascular disease morbidity and mortality in diabetic patients,and it is one of the core pathological features of diabetes-induced vascular damage and remodeling1.Although several mechanisms,such as oxidative stress and inflammation,have been proposed to play a role in the occurrence and development of VC,and treatment strategies targeting these underlying factors have been developed,the effectiveness of these therapies remains limited and faces many challenges.
Drug discovery remains a protracted and capital-intensive process, primarily hindered by inefficiencies in drug screening. Microfluidic technology provides a promising approach for in vitro drug screening, enabling physiologically relevant, high-throughput, and cost-effective analysis by mimicking key aspects of cellular microenvironments. The synergistic integration of artificial intelligence (AI) with microfluidics constitutes a pivotal advancement in biomedical analysis. The convergence of the two facilitates automated data analysis, complex pattern recognition, and intelligent experimental control, thereby accelerating drug screening and contributing to enhanced precision. This review systematically presents the latest advancements in AI-assisted microfluidic drug screening, organized by increasing biological complexity: from single-cell analysis (1D), multicellular arrays (2D), and spheroids (3D), to sophisticated Organ-on-a-chip (OoC, 3D+) platforms. We detail how AI algorithms promote screening throughput, sensitivity, and physiological relevance at each scale. Furthermore, we critically discuss the prevailing challenges, including those related to data, model robustness, interpretability, and system integration. Finally, we outline future directions, highlighting the potential of AI-enhanced microfluidics to further advance precision drug discovery and biomedical research. We believe this timely review will offer a useful reference for researchers working in the interdisciplinary field of AI, microfluidics, and pharmacology.
Intranasal vaccines specifically eliciting mucosal immunity in the upper respiratory tract have shown advantages in protecting against respiratory virus invasion. Yet, no clinically licensed intranasal adjuvant remains a major hurdle for the development of intranasal vaccines with low immunogenic antigens like subunit vaccines. Here, we show that liposomes loading simvastatin (Lipo-SV) serve as potent mucosal adjuvants for the intranasal liposomal subunit vaccine encapsulating the hemagglutinin 1 (HA1) glycoprotein of A/PR/8/34 (PR8) H1N1 influenza (Lipo-HA1), providing robust protection against the lethal PR8 H1N1 infection. Compared to cholera toxin subunit B (CTB), the only mucosal adjuvant used in humans, the Lipo-SV substantiate intranasal Lipo-HA1 vaccines to elicit robust systemic and local mucosal immune responses. The underlying mechanism of the adjuvanticity of Lipo-SV involves the increased transcytosis of antigens by inhibiting the geranylgeranylation of RAB5 and RAB7B GTPases in nasal epithelial cells. Moreover, Lipo-SV enhance the submucosal recruitment of dendritic cell for antigen uptake via the Toll-like receptor 4-dependent pathway. Unlike CTB, intranasal Lipo-SV do not induce inflammation in the lung or the inflammatory cytokines in the central nervous system. Our results present a paradigm of design of mucosal adjuvant to target the mucosal epithelial cells in addition to the antigen-presenting cells.
Bacterial enteritis is a specific gastrointestinal tract disorder caused by pathogenic bacterial infection, which not only disrupts the commensal microbiota but also contributes to cascaded complications. Here, we prepared polyethyleneimine (PEI)-based mesoporous silica nanostructures, co-modified with -SH and -S-S- groups, to simultaneously eradicate the pathogenic bacteria, regulate the immune response, and reprogram the inflammatory microenvironment in the infected intestine. Referring to the multivalent sulfur modification, the -S-S- group, with its oxidizability, perturbs the glutathione balance within bacteria, while the combined reductive capacity of -SH and -S-S- scavenges excessive reactive oxygen species and mitigates inflammation-induced damage. Additionally, the well-developed nanopores with a positively charged PEI network facilitate the absorption of bacterial lipopolysaccharide, lipopeptides, flagella and cell-free DNA through hydrogen bonding and electrostatic interactions. Furthermore, the biosilica nanostructures enable the efficient encapsulation of conventional antibacterial agents, such as berberine chloride and norfloxacin, thereby achieving targeted delivery and reducing side effects, which represents a promising strategy for next-generation antimicrobial therapies.
Phosphoglycerate kinase 1 (PGK1) is traditionally recognized for its pivotal role in glycolysis. Our findings reveal that PGK1 also functions as a protein kinase phosphorylating valosin-containing protein (VCP) at S746, which subsequently reduces Beclin 1 deubiquitination and impairs autophagy. Inhibition of PGK1 initiates autophagy in T315I-mutant chronic myeloid leukemia (CML) cells, thereby enhancing their sensitivity to first-generation Tyrosine Kinase Inhibitor (TKI) imatinib and third-generation TKI ponatinib. Despite the significant clinical implications, few PGK1-targeting inhibitors have been approved for clinical use to date. Through a comprehensive high-throughput screening of ∼20,000 natural compounds, we identified flavonoid as potent inhibitors of the enzymatic activity of PGK1. Subsequent structural optimization of these flavonoid derivatives led to the development of CPU-216, a compound that binds to the GLU344 and PHE292 residues of PGK1, effectively inhibiting its enzymatic and kinase activity. Notably, CPU-216 induces autophagy via VCP and Beclin 1 in CML-T315I cells, enhancing their responsiveness to TKIs. These discoveries propose a novel therapeutic strategy for T315I-mutant CML, underscoring the potential to develop targeted treatments that leverage the kinase functions of PGK1.
Terpenoids exhibit diverse biological activities and thus have a wide range of pharmacological applications. In modern drug discovery, data-driven deep models play a crucial role in facilitating efficient feature representation and knowledge inference. To explore the uncharted bioactivity space of terpenoids, the construction of a multi-dimensional relational terpenoid database is essential for mapping terpenoid-bioactivity profiles. In this study, we first constructed a large-scale biological knowledge graph by integrating various data types, including terpenoid compounds, protein targets, cellular targets, genes, diseases, and their interrelationships. Subsequently, we developed a network-based disease prediction model, as well as optimized multiple compound-protein interaction prediction tools to extend the framework for activity research. These resources have been deployed on a user-friendly web platform (TeroACT) accessible at: http://terokit.qmclab.com/teroact/. Using in silico models within the TeroACT platform, we screened multiple terpenoid molecules for anti-melanoma activity. In vitro and in vivo animal models further validated the anti-migration and anti-proliferative effects of mollugin and columbianadin in melanoma. Additionally, integrated computational screening and experimental approaches identified numerous terpenoids with anti-inflammatory properties. In this sense, TeroACT fills the gap in terpenoid bioactivity study by providing a comprehensive data resource and AI-driven drug discovery tools.
