Smart medicine最新文献

{"title":"A Selective Pro-Oxidant Drives Redox Reprogramming to Induce Ferroptosis and Immune Remodeling in Glioblastoma.","authors":"Shilpi Singh, Iteeshree Mohapatra, Katelyn Kim, Raza Ali Naqvi, Devanjan Dey, Laura Mohapatra, Davis Seelig, Afsar R Naqvi, Amar Singh, Kathleen Boris-Lawrie, Stefan Kim, Gatikrushna Singh","doi":"10.1002/smmd.70058","DOIUrl":"https://doi.org/10.1002/smmd.70058","url":null,"abstract":"<p><p>Glioblastoma remains a highly lethal malignancy characterized by profound therapeutic resistance driven, in part, by adaptive redox homeostasis. Although elevated reactive oxygen species support tumor progression, glioblastoma relies on robust antioxidant systems including the <i>SLC7A11</i>-<i>GPX4</i> axis to buffer oxidative stress, creating a targetable vulnerability. Here, we investigate <i>Rosasina</i>, a sodium-chlorite (NaClO₂)-derived, redox-active small molecule, as a selective pro-oxidant strategy to disrupt glioblastoma antioxidant resilience and induce ferroptotic cell death. <i>Rosasina</i> preferentially increased intracellular ROS in glioblastoma cells relative to normal human astrocytes, with hydrogen peroxide representing the predominant ROS species. This oxidative shift was accompanied by expansion of the labile iron pool and enhanced lipid peroxidation. In orthotopic glioblastoma models, <i>Rosasina</i> was well tolerated, significantly reduced tumor growth, prolonged survival, and exhibited no evidence of treatment-related systemic toxicity, with preserved histological integrity of major organs. Mechanistically, <i>Rosasina</i> induces a coordinated pro-ferroptotic transcriptional program, characterized by upregulation of iron uptake and lipid peroxidation pathways (<i>NCOA4, NOX5, ACSL4, TFRC</i>), alongside suppression of antioxidant defenses, including <i>GPX4, GCH1, SCD1</i>, and <i>SLC7A11</i>. In addition to its tumor-intrinsic effects, <i>Rosasina</i> promoted macrophage polarization toward an anti-tumor, pro-inflammatory M1-like phenotype without compromising macrophage viability, suggesting a potential role in tumor immune microenvironment reprogramming. Collectively, these findings establish <i>Rosasina</i> as a redox-directed therapeutic that selectively exploits the oxidative vulnerabilities of glioblastoma to induce ferroptosis simultaneously promoting antitumor immune reprogramming. This study provides a mechanistic framework for the development of redox-targeted therapies for glioblastoma.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 5","pages":"e70058"},"PeriodicalIF":12.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hierarchical Cascade-Activated Microneedle Patches for Photothermal and Chemotherapy.","authors":"Gaizhen Kuang, Wenzhao Li, Yu Wang, Qingfei Zhang, Hua Jiang","doi":"10.1002/smmd.70059","DOIUrl":"https://doi.org/10.1002/smmd.70059","url":null,"abstract":"<p><p>Chemotherapy and photothermal therapy (PTT) are recognized as effective strategies in cancer treatment. However, the challenge remains in effectively targeting these therapeutic modalities to the tumor site to improve therapeutic effects. Here, a novel hierarchical cascade-activated microneedle (MN) patch (MN_DOX@M_ICG) for photothermal and bioorthogonal chemotherapy was developed. The MN patch was fabricated by integrating hydrogel microspheres (M_ICG) containing tetrazine-functionalized indocyanine green (Tz-ICG) into the MN arrays. Upon irradiation with near-infrared light, Tz-ICG with high photothermal conversion efficiency can elevate the temperature of MN, facilitate PTT, and trigger the release of <i>trans</i>-cyclooctene-conjugated doxorubicin (TCO-DOX) encapsulated in MN. Then, the gradually released Tz-ICG from M_ICG can react with TCO-DOX via a specific inverse electron-demand Diels-Alder bioorthogonal reaction, thereby restoring the anticancer activity of DOX. Consequently, MN_DOX@M_ICG can efficiently eradicate tumor cells in vitro and significantly inhibit the growth of postsurgical melanoma by combining PTT with bioorthogonal chemotherapy. These findings highlight the practical value of such a hierarchical cascade-activated MN patch for versatile drug delivery and biomedical applications.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 5","pages":"e70059"},"PeriodicalIF":12.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 3D-Bioprinted, Cell-Guiding Hydrogel Patch Promotes Functional Repair of Abdominal Incisions via Anisotropic ECM Remodeling.","authors":"Tianxing Gong, Hao Li, Xueqiang Peng, Xinwei Liu, Xinyan Zhang, Qiushi Tang, Stephanie Willerth, Mario Taba Junior, Ricardo M Carvalho, Hailong Yu, Shibo Wei, Hangyu Li","doi":"10.1002/smmd.70056","DOIUrl":"10.1002/smmd.70056","url":null,"abstract":"<p><p>Incisional hernias result from disorganized, mechanically weak scar tissue following abdominal surgery. Current surgical meshes are suboptimal and fail to guide functional regeneration, creating a critical need for new therapeutic approaches. This study introduces an architecture-guided regenerative repair strategy that enhances abdominal incision repair. We developed a Hydrogel-based Architecture-guided Regenerative Patch (HARP) featuring 3D-bioprinted, parallel-aligned filaments that are oriented perpendicular to the incision to provide architectural guidance. The HARP was fabricated from a novel gelatin/dialdehyde cellulose bioink loaded with fibroblasts and TGF-β1 and evaluated in vitro and in a rat abdominal incision model. In vivo, the HARP accelerated healing and yielded a twofold increase in mechanical strength over controls. This resulted from the guided deposition of a dense, anisotropic, type I collagen-rich matrix that resembled native tissue. Our findings support a role for architectural guidance in functional abdominal wall repair, providing a proof of concept for a regenerative repair strategy with the potential to reduce incisional hernia risk.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 5","pages":"e70056"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organ-on-a-Chip Technology: Advances in Modeling Inflammation, Neurovascularization and Nociception in Human Intervertebral Disc Degeneration.","authors":"Izzat Zulkiflee, Nurul Fariha Za'aba, Abhay Pandit, Isma Liza Mohd Isa","doi":"10.1002/smmd.70051","DOIUrl":"10.1002/smmd.70051","url":null,"abstract":"<p><p>An organ-on-a-chip platform has emerged as an advanced in vitro model that replicates organ-level structures within physiologically relevant human microenvironments. In this review, we focus on intervertebral disc (IVD) degeneration, a leading cause of chronic low back pain, providing a comprehensive overview of the current understanding of IVD anatomy, physiology, and pathogenesis. We review conventional in vitro, ex vivo, and in vivo models, which have expanded our understanding; however, they inadequately reproduce the human phenotype, heterogeneous disc composition and anatomy, which comprises nucleus pulposus (NP) and annulus fibrosus (AF) with neovascularization and sensory innervation within the three-dimensional (3D) degenerative microenvironment. We emphasize a disc-on-a-chip platform to address these limitations, which integrates microfluidics and biomimetic ECM-based hydrogels within a controlled microenvironment to miniaturize the disc. It offers a promising platform to simulate the pathological disc milieu by incorporating gradient control of key signaling molecules implicated in disc degeneration. These include a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) degradation; tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)-driven inflammation via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); vascular endothelial growth factor (VEGF)-promoted angiogenesis; and nerve growth factor (NGF)- and brain-derived neurotrophic factor (BDNF)-mediated sensory innervation and sensitization, thus contributing to nociception. Collectively, disc-on-a-chip offers a next-generation in vitro model for investigating mechanisms relating to ECM degradation, inflammation, innervation, vascularization, and nociception underlying IVD degeneration, enabling precision preclinical therapeutic evaluations.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70051"},"PeriodicalIF":12.8,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148876831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limited Added Effect of Proline-Rich P6 Peptide to Cross-Linked Hyaluronic Acid After Partial Lateral Meniscectomy in Sheep.","authors":"Augustine Mark Saiz, Reem Jamous, Sabine Stötzel, Maryam Rahmati, Leonard Volrath Holmboe, Soren David Johnson, Øystein Øvrebø, Angela De Lauretis, Thaqif El Khassawna, Liebert P Nogueira, Maria Permuy, Fernando Muñoz, Antonio Gonzalez Cantalapiedra, Carlotta De Luca, Ståle Petter Lyngstadaas, Håvard Jostein Haugen","doi":"10.1002/smmd.70048","DOIUrl":"10.1002/smmd.70048","url":null,"abstract":"<p><p>This study evaluates whether a proline-rich P6 peptide provides added benefit to a cross-linked hyaluronic acid (HA) hydrogel after partial lateral meniscectomy-associated osteoarthritis-like change in sheep. The corrected four-group framework includes Intact no-surgery/no-injection reference knees (<i>n</i> = 7) and 16 surgically injured knees from eight sheep assigned to Mnx (meniscectomy only, <i>n</i> = 4), Mnx + HA (<i>n</i> = 6), or Mnx + HA + P6 (<i>n</i> = 6). Mnx + HA and Mnx + HA + P6 knees received intra-articular injections at Weeks 0, 1, 2, and 4. Osteochondral tissues were evaluated at Week 12 by microCT, H&E scoring, and histochemical/immunohistochemical image analysis. Endpoint-specific animal- or knee-level models were used, with sheep identity included as a random effect when estimable. HA-based treatment was associated with favorable trabecular microCT patterns after meniscectomy. However, the primary Mnx + HA + P6 versus Mnx + HA contrast was not significant for percent trabecular bone volume/BV/TV (+1.52 percentage points; 95% CI -2.22 to 5.26; <i>p</i> = 0.427). Histology and IHC/histochemical findings showed selected exploratory tissue-pattern signals, including collagen-associated matrix staining, but did not establish consistent peptide-specific superiority. These findings support cross-linked HA as an intra-articular biomaterial platform while defining requirements for confirmatory HA-peptide hydrogel studies.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70048"},"PeriodicalIF":12.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13517024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regenerative Microbiology: Harnessing Bacterial Antagonism and Spatiotemporal Signaling for Diabetic Wound Repair.","authors":"Sabri Saeed Sanabani","doi":"10.1002/smmd.70044","DOIUrl":"https://doi.org/10.1002/smmd.70044","url":null,"abstract":"<p><p>Chronic diabetic foot ulcers represent a persistent clinical challenge characterized by a \"locked\" inflammatory phase, biofilm-mediated infection, and impaired tissue regeneration. Because conventional antibiotic and debridement therapies fail to resolve dysbiosis or stimulate healing, microbial antagonism has emerged as a potent biological principle for wound restoration. This narrative review integrates ecological evidence and mechanistic insights from animal models and early human studies to explore how beneficial microorganisms, including probiotics, bacteriophages, and competitive consortia, actively reshape diabetic wound environments. We examined the multifaceted mechanisms of these interactions, ranging from direct pathogen inhibition to host immunomodulation and metabolic signaling via conserved pathways such as the p40/epidermal growth factor receptor (EGFR)/PI3K axis. To address significant translational barriers, we introduce a \"Regenerative Microbiology\" framework that emphasizes spatiotemporal coordination and precision stratification. By tailoring the use of live biotherapeutics or metabolically independent postbiotics to a patient's vascular and microbial profiles, this approach offers a strategic roadmap for transforming the management of infection-driven tissue damage in chronic diseases.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70044"},"PeriodicalIF":12.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Treatment of Degenerative Eye Diseases at the Nanoscale.","authors":"Li Yao Jin, Evashiniee G P Selvam, Qinsong Mei, Chi D Luu, Yeannie H Y Yap, Daniel B L Teh","doi":"10.1002/smmd.70050","DOIUrl":"https://doi.org/10.1002/smmd.70050","url":null,"abstract":"<p><p>Degenerative ocular diseases are characterized by a convergence of molecular perturbations, including oxidative stress, chronic inflammation, failure of proteostasis, mitochondrial dysfunction, abnormal angiogenic signaling, and biomechanical remodeling. The eye's unique architecture, sealed by the blood-retina barrier, presents formidable anatomical and cellular topological challenges to achieving long-term curative therapeutics. Nanotechnology offers an advantage in potential therapy: by utilizing carriers in the nanometer size range and leveraging on appropriate surface modifications, it can effectively overcome these physiological barriers for enhanced, controlled, and targeted treatment. Clinical and preclinical systems such as antioxidant nanoparticles, sustained release implants, anti-angiogenic nanoplatforms, multifunctional nanocomposites, and regenerative scaffolds illustrate how nanotechnology can overcome limitations in bioavailability, tissue penetration, and pathway specificity in degenerative ocular diseases. Diagnostic advances that include plasmonic contrast agents, quantum dots, graphene biosensors, smart contact lenses, and photothermal neuromodulators further demonstrate continuous molecular surveillance and responsive intervention. Emerging materials such as DNA origami and magnetoelectric nanosystems expand this capability by enabling direct modulation of transcriptional, metabolic, and neuroelectrical pathways. Together, these developments position nanotechnology as a powerful strategy for addressing the molecular origins of ocular degeneration while also highlighting ongoing challenges in long term safety, device stability, manufacturing reproducibility, and regulatory standardization.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70050"},"PeriodicalIF":12.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent Dietary Supplementation of Omega-3 Polyunsaturated Fatty Acids Alleviates PTSD-Like Fear Memory and Affective Dysregulation in Rats.","authors":"Wenjing Li, Yi Yin, Jie Li, Ziwei Yao, Siqi Wang, Yinan Jin, Lihua Bian, Jianyou Guo","doi":"10.1002/smmd.70049","DOIUrl":"10.1002/smmd.70049","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder affecting approximately 3.9% of individuals worldwide over their lifetimes. Since adolescence is characterized by ongoing brain maturation and increased responsiveness to environmental stressors, this developmental stage may provide an important window for PTSD intervention. Growing evidence supports an association between ω-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and the restoration of stress-induced neural damage. However, how ω-3 PUFA supplementation during adolescence affects adult susceptibility to PTSD remains poorly understood. Here, we observed significantly reduced DHA and EPA concentrations in the prefrontal cortex (PFC) and serum of PTSD-susceptible rats. Providing 1.2% DHA and EPA in the adolescent diet significantly reduced PTSD-like phenotypes in adulthood, including excessive fear memory retention, depressive-like and anxiety-like behaviors, while also reducing serum levels of proinflammatory cytokines. These phenotypic and inflammatory improvements were associated with changes in the gut microbiome, including its composition and diversity. DHA/EPA supplementation was also linked to alterations in multiple lipid species, with serum phosphatidylcholine levels showing a significant correlation with fear memory expression. Moreover, we observed dysregulation of the PI3K/AKT/mTOR pathway in the PFC of PTSD-like rats, which was less pronounced in DHA/EPA-supplemented animals. Collectively, these findings provide the first evidence relating adolescent ω-3 PUFA status to PTSD-like phenotypes in adulthood. It further identifies that gut microbiota composition, lipid metabolic profiles (notably phosphatidylcholine), and prefrontal PI3K/AKT/mTOR signaling are correlated with these behavioral outcomes, suggesting that these systems may collectively contribute to trauma resilience.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70049"},"PeriodicalIF":12.8,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MacAma: Multi-AI Agent as a Co-Scientist for Automated Meta-Analysis.","authors":"Yilin Yuan, Pingping Li, Yang Wang, Boyuan Zheng, Yingshuang Liu, Dongjin Yang, Hai Lin, Min Wu, Qi Zhao, Jianwei Shuai, Gen Yang","doi":"10.1002/smmd.70045","DOIUrl":"10.1002/smmd.70045","url":null,"abstract":"<p><p>Meta-analysis is fundamental to evidence-based medicine, yet traditional workflows remain labor-intensive and susceptible to bias. Although LLM-based research agents offer opportunities for workflow automation, they often lack the data fidelity and methodological traceability required for rigorous quantitative evidence synthesis, particularly when parsing multimodal scientific charts. To address this challenge, we introduce MacAma, a semi-automated multi-agent framework for protocol-constrained and human-verifiable meta-analysis. MacAma operationalizes selected PRISMA 2020 reporting items, PICOS-based eligibility logic, and SYRCLE risk-of-bias domains as structured prompts, decision rules, output fields, and audit records. Critically, MacAma adopts a risk-aware automation strategy: Lower risk, repetitive, and protocol-driven tasks, such as literature screening and drafting, are delegated to AI agents, whereas high-impact steps that directly affect effect-size estimation and statistical conclusions, such as quantitative chart-data extraction, remain subject to expert verification. <i>In a preclinical radiotherapy case study evaluating tumor-related immune outcomes and metastatic potential mediated by circulating tumor cells, MacAma achieved competitive screening performance in the evaluated benchmark and reduced the manual screening burden by over 80% within the current workflow. The case study further demonstrates how structured agent outputs, predefined criteria, and audit records can</i> <i>support transparent screening, data extraction, statistical synthesis, and manuscript drafting</i>. These results suggest that MacAma may provide a scalable and auditable framework for AI-assisted meta-analysis, although important limitations remain in full-text access, quantitative chart data extraction, and expert interpretation of heterogeneity. MacAma is open-source and available at https://github.com/YilinYuan/MacAma.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70045"},"PeriodicalIF":12.8,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13431750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Contact Transspatial Regulatory Function of the Extracellular Matrix.","authors":"Ting Cao, Chen Yang, Zhengyang Wang, Changmin Shao, Ziye Xu, Baode Chen, Jiayu Zhang, Yongcheng Wang, Fangfu Ye","doi":"10.1002/smmd.70046","DOIUrl":"10.1002/smmd.70046","url":null,"abstract":"<p><p>As a crucial biological material, the extracellular matrix (ECM) constitutes a major part of the extracellular microenvironment, offering both structural support and essential biological signals to surrounding cells. Research into ECM properties not only deepens our understanding of cellular behavior and metabolism but also opens new avenues for studying disease mechanisms and therapies. In this work, we report a previously unrecognized function of ECM by leveraging a three-dimensional spatial cavity structure. It is termed \"Non-contact Transspatial Regulatory\" (nCTR), referring to the ECM that remotely regulates cells without traditional direct physical contact. Systematic investigation and validation of key factors reveal that nCTR strongly depends on the 3D spatial distance between ECM and cells, governed by both physical spatial confinement and chemical signaling exchange. The process involves multiple components, pathways, and mechanisms, with macropinocytosis playing a dominant role. This newly identified function of the ECM offers a fresh perspective on cellular behavior and will undoubtedly open a new frontier in the cellular microenvironment studies.</p>","PeriodicalId":74816,"journal":{"name":"Smart medicine","volume":"5 4","pages":"e70046"},"PeriodicalIF":12.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13410397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148623021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}