Metabolic reprogramming is a hallmark of cancer and serves as a potential therapeutic target, whereas the metabolic feature of acute lymphoblastic leukemia (ALL) was marginally addressed. Based on RNA-sequencing data in an in-house and external cohort, we aimed to dissect metabolic feature subtypes (MFS) of ALL, which were further cross-validated through a transcriptomics-metabolomics-functional systematic framework. ALL were stratified into three subtypes, of which MFS1 was polysaccharide-metabolic, MFS2 was cold-metabolic, and MFS3 was glycolysis hot-metabolic subtype. Notably, metabolic stratification was significantly associated with patient survival, as 70%-81% overall-survival in MFS1, compared with 25%-56% in MFS2 and MFS3 (MFS1 vs. MFS2, MFS3, p < 0.001). Additional analysis revealed the association between MFSs and clinical features, molecular mutation, and copy number aberration. Metabolic heterogeneity indicated susceptibility to antimetabolite drugs for ALL in vitro. MFS1 was sensitive to antimetabolite drugs for ALL, such as L-asparaginase and 6-mercaptopurine, while MFS2 and MFS3 were resistant. Furthermore, a glycolysis inhibitor reversed the resistance to L-asparaginase and promoted survival in MFS3-patient-derived xenografts. We developed a novel metabolic-stratification, which dissects metabolic profiling, clinical outcome, and therapeutic vulnerability for precision metabolic intervention in ALL.
Abstract Regulating the fate of stem cells (SCs) is a key technical problem in the field of regenerative medicine and tissue engineering, which involves the comprehensive effect of many factors. The commonly used types of SCs were summarized, and the research progress of regulating the fate of SCs through physical factors, biological factors and chemical factors were discussed. It also reviewed the applications and mechanism of SCs in repairing neurodegenerative diseases, optic nerve injury, auditory nerve injury, traumatic peripheral nerve injury, etc. Finally, the future regulatory strategies and development were prospects. The aim is to provide a new idea and method for the treatment of neural regeneration.
Abstract Integrated one‐pot CRISPR‐Cas detection combines isothermal amplification with CRISPR‐Cas‐mediated recognition in a single vessel, streamlining workflows, reducing time, and minimizing contamination risks for point‐of‐care diagnostics. This review systematically outlines current advances and core challenges, focusing on strategies to enhance performance. Existing methods achieve temporal and spatial coordination of amplification and detection through physical compartmentalization, chemical regulation, or enzymatic modulation, effectively mitigating interference between Cas enzymes and amplification systems to boost sensitivity and reliability. Despite progress, issues remain in system compatibility, multiplexing, sample matrix interference, and portable quantitative readouts. Future progress will rely on protein engineering for optimized Cas variants, artificial intelligence‐assisted crRNA design, fully integrated microfluidic devices with lyophilized reagents, and non‐optical detection modalities such as electrochemical or colorimetric.
Sepsis is a heterogeneous syndrome critically driven by immunosuppression, yet lacking personalized prognostic markers and therapeutic targets. Here, we provide evidence to support Metrn beta as a novel prognostic biomarker in sepsis mortality and the function of Metrn beta in modulating macrophage polarization during sepsis immunosuppression. Metrn beta is significantly elevated at disease onset in three independent cohorts comprising adult and pediatric septic patients, and maintained a strong association with 28-day mortality. In murine sepsis, Metrn beta expression was markedly upregulated in peripheral blood, peritoneal lavage fluid, and various organs, exhibiting macrophage-specific co-localization; specific depletion of macrophages reduced systemic Metrn beta levels in vivo. Administration of recombinant murine Metrn beta (rmMetrn beta) aggravated mortality of septic mice in a dose-dependent manner, whereas genetic ablation or neutralization of Metrn beta improved survival by restoring proinflammatory responses and enhancing bacterial clearance. Mechanistically, single-cell RNA sequencing and bulk RNA-seq revealed that Metrn beta orchestrated immune collapse by driving macrophage reprogramming toward an immunosuppressive phenotype. Critically, the adverse effects of Metrn beta in sepsis were mediated through its interaction with c-Kit on macrophages. Collectively, our findings establish Metrn beta as a key prognostic biomarker and validate the targeted blockade of the Metrn beta-c-Kit axis as an effective therapeutic approach for immunocompromised sepsis.
Growing evidence implicates diabetic tubulopathy (DT), driven by tubular atrophy and interstitial fibrosis, as a major determinant of renal insufficiency and disease outcome in diabetic kidney disease (DKD). This perspective underscores the need to elucidate tubular-specific pathogenic mechanisms. An emerging perspective suggests that mitochondrial dysfunction is an early event in DKD, although the precise pathological mechanism remains unknown. Our previous work identified glycogen synthase kinase 3 beta (GSK3 beta) as a potential novel biomarker for DKD. Thus, we further revealed that GSK3 beta was hyperactivated in the renal tubule of DKD, which was positively correlated with early mitochondrial dysfunction. Conversely, therapeutic targeting of GSK3 beta with TDZD-8 or genetic silencing attenuated early mitochondrial dysfunction and delayed DT. Mechanistically, the key downstream effector through which GSK3 beta accelerates DKD progression is the Transcription factor EB (TFEB) signaling pathway. Specifically, upon activation, GSK3 beta inhibits the nuclear translocation of TFEB, leading to dysregulated TFEB transcriptional function, which in turn mediates early mitochondrial damage in experimental models of DKD. This is manifested as alterations in mitochondrial morphology, dynamics, mitophagy, and reactive oxygen species production. Therefore, GSK3 beta overexpression accelerates early mitochondrial dysfunction in renal tubules during DKD by impairing TFEB nuclear translocation, providing a rationale for targeting the GSK3 beta/TFEB axis to preserve mitochondrial fitness in DT.
Abstract Mitochondria are central regulators of cellular energy metabolism, redox homeostasis, and programmed cell death, making them highly attractive targets for cancer therapy. Rapid advances in nanotechnology have enabled the rational design of mitochondria‐targeted nanomedicines for subcellularly precise drug delivery. At present, mitochondrial targeting is mainly achieved by surface modification with lipophilic cations or functional peptides. Nanoparticles (NPs) equipped with these moieties can preferentially accumulate in tumor‐cell mitochondria and enhance antitumor efficacy through multiple mechanisms, including disruption of redox balance, interference with energy metabolism, damage to mitochondrial structure, and induction of immunogenic cell death. These systems may also reduce systemic toxicity and help overcome therapeutic resistance. However, a comprehensive framework for the rational design of mitochondria‐targeted nanoparticles remains lacking. In this review, we summarize current design strategies for mitochondria‐targeted nanoparticles, discuss their multidimensional antitumor mechanisms, and highlight recent advances in their applications in cancer therapy. We further examine the major challenges related to targeting efficiency, biosafety, and clinical translation. This review aims to provide a useful reference for the development of next‐generation mitochondria‐targeted nanotherapeutics with improved precision and efficacy.
Abstract Extracellular vesicles (EVs) are cell‐derived particles delimited by a lipid bilayer and containing a wide variety of cargos that cannot replicate independently. Their key role as mediators of intercellular communication implicates them in a broad spectrum of physiological and pathological processes. In recent years, EVs have gained increasing attention as potential biomarkers, therapeutic targets and drugs delivery vehicles. However, the successful translation of EV‐based strategies from bench to bedside requires a deeper understanding of EV composition and the biogenesis mechanisms. A particularly promising and actively investigated avenue in EV research is the targeted inhibition of EV biogenesis. Modulating these processes not only provides valuable tools for dissecting EV functions in vitro and in vivo, but also opens new therapeutic possibilities, especially in diseases where EVs contribute to pathogenesis, such as cancer, neurodegeneration, inflammation and infectious diseases. Identifying and characterizing compounds that interfere with EV biogenesis is therefore of high relevance, both for fundamental research and clinical applications. This review aims to contribute to the field by offering a comprehensive overview of the most studied EV inhibitors, highlighting their mechanisms of action, experimental utility, and potential for therapeutic exploitation. Particular attention is given to their advantages and limitations as modulators of EV biogenesis, with the goal of guiding future research toward more effective and selective strategies.
Abstract Intracerebral hemorrhage (ICH) is a severe neurological condition characterized by high mortality and long‐term disability. The pathophysiology of ICH involves not only primary hematoma formation but also secondary injury mechanisms such as blood–brain barrier disruption, oxidative stress, excitotoxicity, and neuroinflammation. Hematoma‐derived factors like hemoglobin, iron, and thrombin, together with pro‐inflammatory cytokines from activated glial and immune cells, exacerbate neurovascular dysfunction. Emerging research highlights the role of the bone‐brain axis, where bone marrow‐derived cells and osteokines influence systemic inflammation, angiogenesis, and tissue repair. Hydrogel‐based drug delivery systems (HDDS) have gained attention for their potential to address these challenges, offering controlled release, biocompatibility, and targeted delivery. This review summarizes recent advancements in hydrogel‐based therapeutic strategies for ICH treatment, focusing on structure‐activity relationships and the integration of bone‐brain axis modulation for enhanced neuroregeneration. We discuss key translational barriers, including biosafety, manufacturing scalability, and inter‐patient heterogeneity. Future advances are expected to rely on the development of dynamic, microenvironment‐responsive hydrogels that can synchronize drug release with stage‐specific pathological cues, improving therapeutic precision. Moreover, combining HDDS with multimodal therapies and minimally invasive neurosurgical techniques may further enhance clinical outcomes. The potential for HDDS to target both local brain injury and systemic inter‐organ crosstalk represents a promising direction for advancing clinical applications in ICH.
Abstract Inflammatory bowel disease (IBD) is characterized by gut microbial dysbiosis, dysregulated host immune responses and increased susceptibility to certain intestinal infections. These factors complicate the distinction between active infection, inflammatory flare, and mixed inflammatory infectious states. Conventional diagnostics remain essential in clinical practice, but a single test is often insufficient to separate colonization, true infection, and inflammation‐related symptoms. This review summarizes current evidence on multi‐omics biomarkers relevant to intestinal infection and inflammation in IBD, including metagenomics, metabolomics, proteomics, single‐cell RNA sequencing, spatial transcriptomics and radiomics features. Biomarkers linked more closely to infection are considered alongside those that mainly reflect inflammatory activity, with attention to areas of overlap. The review also examines the degree of validation across studies, major sources of heterogeneity and confounding, and the strengths and limitations of emerging diagnostic platforms and artificial intelligence (AI) assisted integrative approaches. Overall, multi‐omics strategies may improve diagnostic stratification and deepen understanding of disease mechanisms in IBD. However, most candidate biomarkers and related platforms remain insufficiently validated for routine clinical use.
Abstract Artificial cells have emerged as a class of promising bioactive materials that recapitulate key structural and functional features of natural cells, serving as an effective alternative to address the inherent bottlenecks of conventional biomaterials in biomedical research, particularly in cancer theranostics. Fabricated primarily via bottom‐up strategies, these bioactive constructs enable modular assembly of functional biomaterials to build hierarchical systems spanning artificial organelles, diverse artificial cells and prototissues, endowing artificial cells with tuneable mechanical properties, programmable environmental responsiveness and precise targeted delivery capabilities. Unlike traditional cancer diagnostic and therapeutic agents that suffer from poor tumour specificity, rapid systemic clearance and severe off‐target effects, artificial cells leverage their biomimetic design to achieve prolonged circulatory retention, precise tumour site accumulation, and controlled release of diagnostic probes and therapeutic payloads. This review systematically explores the major types of artificial cells, modular bottom‐up construction methods, and advanced biomimetic behaviours of artificial cell systems. Additionally, it highlights their cutting‐edge applications in integrated cancer theranostics, including tumour biomarker sensing, targeted drug delivery, and immunomodulatory therapy. Finally, the review addresses key challenges and future directions to accelerate their clinical translation in oncology.
Abstract Hematologic malignancies (HMs) are aggressive neoplasms originating from lymphoid or myeloid lineages. They are characterized by heterogeneous clinical manifestations, high refractoriness, and frequent relapse. Recent advances in extracellular vesicle (EV) research have revealed their translational potential in improving the diagnosis, prognosis, and treatment of HMs. EVs are nanoscale membrane‐bound particles secreted by cells. They carry bioactive cargo, including nucleic acids, proteins, and metabolites, and mediate intercellular communication. In HMs, EVs play essential roles in tumor initiation, progression, metastasis, angiogenesis, metabolic reprogramming, and drug resistance, positioning them as pivotal contributors to disease pathogenesis. Leveraging their functional versatility and disease‐specific molecular signatures, EVs show promise as non‐invasive biomarkers for early detection and disease monitoring. They also represent potential therapeutic targets to disrupt tumor‐microenvironment crosstalk, and as engineered drug delivery systems for precision medicine. This review systematically examines the pathobiological functions of EVs in HMs and highlights emerging clinical applications, offering valuable insights to guide future research.
Abstract Conventional drug delivery methods, such as oral administration and intravenous injection, are associated with several challenges including high systemic toxicity, difficulty in dosage control, and delayed therapeutic responses. These issues limit both the efficacy of treatments and patient compliance, thus becoming a bottleneck in the advancement of precision medicine. In recent years, implantable drug delivery systems (IDDS) have emerged as a promising frontier at the intersection of precision medicine and medical engineering. Through in vivo implantation coupled with signal response mechanisms, IDDS facilitates targeted drug delivery, dynamic regulation, and real‐time responsiveness. These significantly enhance therapeutic efficacy while reducing toxicity levels, offering a new path to address the limitations inherent in traditional delivery methods. This article reviews the research progress of IDDS. The technical principles and module innovations are systematically elaborated based on three mechanisms: endogenous response, exogenous triggering, and closed‐loop control. Furthermore, it explores the pivotal role that flexibilization and miniaturization of IDDS play in improving biocompatibility, tissue adhesion capabilities, and spatial adaptability. The article also summarizes application examples within typical disease models while analyzing core challenges related to clinical translation. Finally, it anticipates future development directions for integrating medical engineering into this evolving field.
Abstract Fusobacterium nucleatum (F. nucleatum), recognized for its opportunistic pathogenicity, is a prevalent pathogen implicated in several diseases. Emerging evidence highlights the crucial role of F. nucleatum–derived extracellular vesicles (F. nucleatum EVs) in mediating virulence and serving as carriers of diverse bioactive components that facilitate host–pathogen interactions. F. nucleatum EVs can disseminate from the oral cavity to the gastrointestinal tract and joints, promoting the onset and progression of oral inflammatory diseases, head and neck squamous cell carcinoma, rheumatoid arthritis, inflammatory bowel disease, and colorectal cancer through various signaling pathways. A deeper understanding of F. nucleatum EVs will advance the understanding of the pathogenesis of related diseases and inform the development of effective infection control strategies. This review systematically summarizes recent progress in the biogenesis, molecular composition, and pathogenic roles of F. nucleatum EVs across various disease contexts and evaluates potential strategies for the diagnosis, treatment, and management of conditions involving F. nucleatum and its EVs.
Abstract The integration of three‐dimensional (3D) printing and bioprinting technologies has significantly reshaped the landscape of gynecological medicine, offering innovative strategies to address clinical challenges related to reproductive organ disorders and gynecological malignancies. This review systematically examines recent advancements and clinical applications of 3D printing in female reproductive health, with a focus on tissue engineering and personalized medical solutions for complex gynecological conditions. Specifically, it discusses cutting‐edge developments in 3D bioprinting techniques tailored for regenerating uterine endometrium, ovarian, cervical, vaginal, and pelvic tissues, while highlighting the crucial role of advanced biomaterials, bioinks, and patient‐specific scaffold fabrication. Furthermore, it critically evaluates personalized 3D printing approaches in gynecological oncology, including targeted drug delivery systems, precision brachytherapy applicators, and anatomical models designed to improve surgical outcomes and therapeutic efficacy in endometrial, cervical, and ovarian cancers. Despite significant technological advancements, persistent challenges remain, such as limitations in materials, control over drug release, vascularization strategies, and regulatory hurdles. The review concludes by outlining future research directions, focusing on the integration of advanced imaging, artificial intelligence‐driven design, and multimodal therapeutic platforms. Ultimately, the incorporation of these sophisticated 3D printing solutions into routine clinical practice promises to set new benchmarks in precision gynecology, substantially enhancing patient‐specific therapeutic outcomes and quality of life.
Abstract The vaginal microbiota plays a critical role in regulating endometrial development, which is key for successful embryo implantation and pregnancy. However, the extent to which the vaginal microbiota contributes to various tissue regeneration‐associated functions of human endometrial stem cells, which play pivotal roles in endometrial development and subsequent endometrial receptivity, remains largely unexplored. Here, we demonstrate that exposure to microbiota‐derived secretory factors enhances key regenerative functions of endometrial stem cells, including self‐renewal, migratory capacity, multilineage differentiation potential, and metabolic activity via upregulation of vascular cell adhesion molecule 1 (VCAM1), which serves as a central regulatory hub, and the subsequent activation of the PI3K/Akt signaling pathway, highlighting a critical microbiota‐driven mechanism governing endometrial stem cell function and tissue regeneration. Functional knockdown of VCAM1 and pharmacological inhibition of the Akt signaling pathway attenuated the microbiota‐driven beneficial effects, confirming their functional roles. Notably, depletion of the vaginal microbiota impaired endometrial development and significantly reduced the clonogenicity of endometrial stem cells in vivo, reinforcing the essential role of microbiota‐derived factors in endometrial homeostasis. These findings provide critical insights into the microbiota‐endometrial stem cell crosstalk and highlight the therapeutic potential of microbiota‐derived secretory factors in stem cell‐based regenerative medicine and reproductive health.
Abstract Cancer remains a significant global health threat. The tumor microenvironment (TME) is a sophisticated ecological niche that exerts a pivotal effect on treatment outcomes. Among the diverse components composing the TME, the intratumoral microbiota (IM) has become a research focus, which can regulate tumor initiation, progression, and therapeutic response. The link between cancer and microorganisms dates back 4000 years. Advanced sequencing technologies have revealed that the unique microbial communities within tumors serve a dual function: directly modulating tumor cell biology via metabolic processes and shaping TME immunity through interactions with immune and matrix components. Their metabolites act as mediators either inducing immunosuppression via immune metabolic reprogramming or triggering systemic immunity through pattern recognition receptors. Consequently, IM imbalances may contribute to immune evasion and therapeutic resistance. This article addresses immunotherapy resistance and treatment failure, systematically exploring the origins and detection methods of IM, elucidating its regulatory mechanisms within the TME, examining its impact on immunotherapy efficacy, assessing the utility of IM in diagnostic biomarker applications, and discussing the technical challenges and a roadmap for further inquiry, directed toward providing a comprehensive framework to advance precision immunotherapy in cancer treatment.
Conventional RNA-based vaccines rely on lipid nanoparticles (LNPs) for delivery; however, concerns exist regarding the potential systemic toxicity of their chemical composition, and their immune-activating capabilities require further enhancement. Inspired by Mg2+ as a key ion for maintaining RNA secondary structure stability, we developed a one-pot method for directly synthesizing a circular RNA-based formulation-adjuvant integrated nanovaccine (CircRNA@FAiNVac) capable of delivering programmed circular RNA (circRNA) based on biomimetic mineralization principles. Specifically, during circRNA rolling circle transcription, the controllable crystallization of magnesium pyrophosphate (MgPPi) nanoparticles was achieved by enhancing the reaction kinetics between ribonucleotide triphosphates and Mg2+, thereby encapsulating circRNA within the nanoparticles and forming a protective carrier that also functions as an adjuvant. Based on the specific hydrolysis of MgPPi by pyrophosphatase, CircRNA@FAiNVac can efficiently release RNA intracellularly, thereby facilitating gene expression. Unlike LNPs, which often contain toxic excipients, the vector structure of CircRNA@FAiNVac consisted only of nucleic acid precursors and ions, exhibiting good biocompatibility and reducing adverse reactions. More importantly, CircRNA@FAiNVac possessed potent immune activation capabilities; its self-adjuvanting activity promoted multimodal immune activation, enhancing both humoral and cellular responses. Animal experiments confirmed that the innovative design of CircRNA@FAiNVac ensured stable and sustained autonomous expression of the SARS-CoV-2 receptor-binding domain, while the nanostructure activated multiple immune pathways, providing potent protection. The formulation-adjuvant integration strategy of CircRNA@FAiNVac based on biomimetic mineralization principles provides an alternative approach for the development of next-generation vaccines. Based on antigen sequence optimization, it enables rapid customized development of vaccines targeting variant strains.
Although the COVID-19 pandemic is now considered over, the virus remains prevalent, and regular, on-time vaccination is recommended. Traditional and RNA-based vaccines have proven lifesaving for millions worldwide; however, their long-term efficacy remains unknown. The unmet need is to identify interventions that mitigate the severity of SARS-CoV-2 infection and associated health complications, including damage to multiple organs. Pro-inflammatory cytokines, including tumor necrosis factor (TNF), play a crucial role in the pathogenesis of COVID-19 and the progression to multiple organ failure. The present study describes the role of Mixed Lineage Kinase 3 (MLK3), a TNF downstream target and mitogen-activated protein kinase upstream regulator, in SARS-CoV-2-induced kidney injury. MLK3 activity was higher in SARS-CoV-2-infected K18-hACE2 mice and in human kidneys, and it positively correlated with kidney injury. MLK3 transcriptionally upregulated TMPRSS2 expression via the NFATc1, and genetic or pharmacological inhibition of MLK3 mitigated SARS-CoV-2 pseudovirus entry into kidney cells. SARS-CoV-2 spike glycoprotein receptor binding domain (Spike-RBD) activated MLK3, thereby regulating IL-17A. Heat shock protein 70 (Hsp70) interacts with MLK3 and regulates Spike-RBD-induced IL-17A production and ultimately apoptosis in kidney cells. Our results suggest that MLK3 inhibitors could serve as a therapeutic intervention in COVID-19 patients with acute kidney injury.
