Theranostics最新文献

{"title":"Spatiotemporally programmed hybrid nano-prodrugs orchestrate multidimensionally synergistic cascade lethality in NSCLC.","authors":"Yan Wang, Chaozheng Zhang, Chen Sun, Yao Chen, Jielu Zhang, Yongsen He, Xue Sun, Jingping Wu, Xiaosong Xu, Xingtong Li, Li Deng, Fang Yan, Lang He, Tianbao Wang, Xin Zhou, Tingting Zhang, Maolin Wang, Jin Liu, Zhizhong Wang, Shilin Chen, Bo Ren, Jun Lu","doi":"10.7150/thno.135204","DOIUrl":"10.7150/thno.135204","url":null,"abstract":"<p><strong>Rationale: </strong>Non-small cell lung cancer (NSCLC) develops a high GSH/GPX4 antioxidant phenotype under persistent oxidative pressure, which suppresses membrane lipid peroxidation and ferroptosis, constituting a core mechanism underlying chemotherapy resistance and suboptimal therapeutic efficacy. Breaking this resistance barrier demands not simply attacking the tumor but disarming the antioxidant defense to intensify oxidative damage and awaken durable antitumor immunity.</p><p><strong>Methods: </strong>A self-assembled nano-prodrug, E-R@ISSL, was engineered by co-assembling a carbamate-linked RGD-modified etoposide (ETP) prodrug and a disulfide-bonded indole derivative conjugated to linoleic acid (LA) at an optimal 1:2 molar ratio. The system thus possesses dual αvβ5/mitochondria targeting with CES2/GSH cascade-responsive drug release. Antitumor activity and mechanisms were evaluated <i>in vitro</i> and in both subcutaneous and orthotopic NSCLC mouse models.</p><p><strong>Results: </strong>E-R@ISSL exhibited efficient αvβ5-mediated internalization and mitochondria-targeted delivery. Upon sequential CES2/GSH-triggered disassembly, E-R@ISSL co-released ETP and LA, reduced the available intracellular GSH pool, and functionally dampened the GSH-dependent GPX4 antioxidant defense. ETP induced DNA double-strand breaks and elevated reactive oxygen species (ROS), while LA expanded the oxidizable lipid pool, synergistically driving lipid peroxidation and ferroptosis. Concurrently, the system activated immunogenic cell death (ICD), promoting dendritic cell maturation and enhancing CD8⁺ T cell infiltration. In orthotopic NSCLC models, E-R@ISSL significantly suppressed tumor progression, prolonged survival, and demonstrated a favorable safety profile with reduced systemic toxicity compared with free ETP.</p><p><strong>Conclusions: </strong>Together, these findings demonstrate that E-R@ISSL achieved coordinated DNA damage, ferroptosis, and ICD induction through its dual-targeted and sequentially activated co-delivery of ETP and LA, concurrently dismantling the GSH/GPX4 antioxidant defense and intensifying oxidative injury. This nano-prodrug thus represents a viable strategy for overcoming treatment resistance and extending durable antitumor responses in NSCLC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8808-8826"},"PeriodicalIF":14.9,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano-flow intracalvariosseous infusion enables skull-to-brain delivery of BBB-impermeable molecular and nanoscale agents in mice and rabbits.","authors":"Ji Hee Kang, O Hyun Lee, Min Suk Shim, Sehoon Kim, Dongyun Shin, Young Tag Ko","doi":"10.7150/thno.138110","DOIUrl":"10.7150/thno.138110","url":null,"abstract":"<p><strong>Rationale: </strong>The blood-brain barrier (BBB) remains a major obstacle to the delivery of therapeutics for central nervous system (CNS) diseases. Although several BBB-penetrating or BBB-bypassing strategies have been investigated, there remains a need for sustained, controllable delivery routes that can support prolonged CNS exposure of BBB-impermeable agents. Recent anatomical studies have shown direct connections between skull bone marrow and brain, suggesting that the skull may serve as an alternative access route to the brain. Here, we assessed the feasibility of sustained intracalvariosseous infusion (ICO) as skull-to-brain delivery approach for BBB-impermeable molecular and nanoscale agents in mice and rabbits.</p><p><strong>Methods: </strong>Four-week ICO was performed using a species-adapted nano-flow pump-cannula configuration that positioned the cannula terminus within the skull diploic space. A positive comparator was established by positioning the terminus beyond the inner skull cortex. Placement was verified by conventional CT and micro-CT. Brain-associated exposure of BBB-impermeable paclitaxel, antisense oligonucleotides and gold nanoparticles was assessed, along with systemic toxicity, bone marrow-derived immune activation, and neuroinflammation.</p><p><strong>Results: </strong>ICO produced measurable brain-associated exposure of all three model agents in both species. Relative to the positive comparator, ICO achieved the highest relative brain-associated exposure for ASO, reaching approximately 24-28% of comparator levels, whereas PTX and AuNP showed lower but detectable exposure. Four-week ICO was not associated with overt hematological, biochemical, histopathological, or neuroinflammatory abnormalities under the present experimental conditions.</p><p><strong>Conclusions: </strong>These findings support the technical feasibility of ICO-based sustained infusion as a skull-to-brain delivery platform for controlled and prolonged CNS exposure of BBB-impermeable molecular and nanoscale agents through an extracerebral skull compartment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8947-8967"},"PeriodicalIF":14.9,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membrane and soluble VTCN1 (B7H4) converge on Src signaling to mediate gemcitabine resistance in intrahepatic cholangiocarcinoma.","authors":"Yi-Ru Pan, Sheng-Hsuan Lin, Yu-Chan Chang, Shih-Ming Jung, Chiao-En Wu, Wen-Kuan Huang, Chun-Nan Yeh","doi":"10.7150/thno.130394","DOIUrl":"10.7150/thno.130394","url":null,"abstract":"<p><strong>Rationale: </strong>A combination of gemcitabine (GEM)-based chemotherapy and an immune checkpoint inhibitor is the standard treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA). However, 70% of patients develop progressive disease following GEM treatment, highlighting the urgent need for therapeutic strategies targeting GEM-resistant (GR) disease.</p><p><strong>Methods: </strong>We established GR iCCA sublines and identified 9 upregulated genes by RNA-sequencing and cDNA microarray. Among the 9 genes, we demonstrated that VTCN1 expression improved GR. The enhanced effect of VTCN1 on GR was validated in a spontaneous rat iCCA model, a xenograft mouse model, an orthotopic mouse model, and iCCA specimens. A phospho-kinase array was used to identify the downstream effector of membrane and soluble VTCN1 (sVTCN1).</p><p><strong>Results: </strong>VTCN1 expression was significantly elevated in GEM non-responders and independently predicted poor progression-free survival (HR = 2.038, P = 0.035). Plasma sVTCN1 levels correlated with tumor VTCN1 expression (<i>r</i> = 0.8752, P = 0.002) and tumor burden (<i>r</i> = 0.7696, P < 0.0001). Mechanistically, membrane-bound VTCN1 directly interacted with integrin β1 to enhance FAK phosphorylation, while sVTCN1 bound EGFR to create a positive feedback loop increasing EGFR phosphorylation. Both pathways converged on Src family kinase activation (Y419 phosphorylation) to drive GR. The VTCN1-Src axis was associated with upregulation of cytosolic 5'-nucleotidase 3 (NT5C3) expression to promote GEM resistance. VTCN1 depletion, Src depletion, or Src inhibition with dasatinib restored GEM sensitivity. Combining VTCN1 antibody or dasatinib with GEM significantly suppressed resistant tumor growth and enhanced CD8⁺ T cell infiltration <i>in vivo</i>.</p><p><strong>Conclusions: </strong>Membrane and soluble VTCN1 drive GR through dual pathways converging on Src activation. VTCN1 represents both a prognostic biomarker and therapeutic target, with Src inhibition providing a rational strategy to overcome chemotherapy resistance in iCCA.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8968-8986"},"PeriodicalIF":14.9,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the <i>in vivo</i> traits of vasculogenic mimicry.","authors":"Mariam-Eleni Oraiopoulou, Thierry L Lefebvre, Eleftheria Tzamali, Thomas R Else, Ian G Cannell, Lorna C Wright, Ellie V Bunce, Cara Brodie, Paul W Sweeney, Luca Porcu, Dominique-Laurent Couturier, Vangelis Sakkalis, Gregory J Hannon, Sarah E Bohndiek","doi":"10.7150/thno.140146","DOIUrl":"10.7150/thno.140146","url":null,"abstract":"<p><p>Vasculogenic mimicry describes the ability of cancer cells to acquire endothelial properties, forming vessel-like channels that facilitate tumour blood supply and can drive resistance to anti-angiogenic therapies. While the molecular drivers have been well-explored in cell cultures and biopsies, vasculogenic mimicry remains a clinical blind spot as no methods exist to detect and monitor such vascular networks non-invasively <i>in vivo</i>.</p><p><strong>Methods: </strong>Here, we introduce a \"topology-first\" framework to define vasculogenic mimicry biomarkers and elucidate its spatiotemporal dynamics using label-free optical and photoacoustic imaging across scales. Using graph theory analysis, we decoded the unique vascular architecture of 4T1 and 4T1-T murine breast cancer models in response to anti-angiogenic treatment with Axitinib.</p><p><strong>Results: </strong>We found stable meshed networks <i>in vitro</i> and blood-containing circular structures <i>in vivo</i> serve as a key topological fingerprint for vasculogenic mimicry, conserved also in human breast cancer models. Crucially, these structures remained remodelling-resistant under anti-vascular therapy, signalling a potential functional mechanism of therapeutic escape.</p><p><strong>Conclusions: </strong>Our results provide the first evidence that vasculogenic mimicry features can be mapped non-invasively through topology, offering a potential future companion diagnostic and method to guide the development of next-generation, multi-target anti-vascular therapeutics.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8633-8649"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactylation at H3K18 drives pathological angiogenesis via metabolic-epigenetic crosstalk in ischemic retinopathy.","authors":"Xin Chen, Yuhan Jiang, Weiqi Qian, Yi Lei, Siyue Chen, Yutian Zhang, Minghui Liang, Yuming Liu, Xiaohong Wang, Ding Ai, Xuyang Yao, Hua Yan","doi":"10.7150/thno.136054","DOIUrl":"10.7150/thno.136054","url":null,"abstract":"<p><p>Ocular neovascular disease, characterized by aberrant angiogenesis in the eye, is a primary cause of global vision impairment and blindness. As the primary barrier exposed to hypoxia-related blood metabolites, endothelial cells (ECs) undergo metabolic reprogramming that drives pathological angiogenesis. However, the epigenetic mechanisms that link EC metabolic dysfunction to retinal vasculopathy remain elusive.</p><p><strong>Methods: </strong>Using western blotting and immunofluorescence analysis of retinal sections/whole-mounts, we confirmed increased histone 3 lactylation at lysine 18 (H3K18la). We subsequently identified downstream target genes through integrated CUT&Tag and RNA sequencing (RNA-seq), assessed their angiogenic regulatory functions using siRNA, and validated the mechanisms <i>in vivo</i> employing adeno-associated virus (AAV)-based gene transfer.</p><p><strong>Results: </strong>Our data indicated that histone lactylation levels were elevated in retinal vascular ECs under hypoxic conditions both <i>in vivo</i> and <i>in vitro</i>. In oxygen-induced retinopathy (OIR) retinal vascular ECs, H3K18la was the most prominent modification. Pharmacological inhibition of glycolysis suppressed H3K18la levels, concurrently abrogating EC activation and neovascularization. Combined CUT&Tag and RNA-seq analyses revealed that ETS1 was a direct transcriptional target governed by H3K18la in retinal ECs. Silencing ETS1 substantially inhibited hypoxia-induced proliferation, migration, sprouting, and tube formation in human retinal microvascular endothelial cells (HRMECs). Crucially, <i>in vivo</i> rescue experiments confirmed that ETS1 overexpression reversed the suppression of pathological neovascularization in OIR mice treated with AAV-Pfkfb3-RNAi.</p><p><strong>Conclusions: </strong>Collectively, this study revealed a lactate-driven epigenetic cascade wherein H3K18la licenses ETS1-dependent pathological angiogenesis, providing a promising therapeutic avenue for ischemic retinal diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8650-8668"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolution of surrogate microspheres in transarterial radioembolization: from SPECT prediction to multimodal AI-guided precision dosimetry.","authors":"Arun Gupta, Andrew C Gordon, Samdeep K Mouli, Robert J Lewandowski, Dong-Hyun Kim","doi":"10.7150/thno.134985","DOIUrl":"10.7150/thno.134985","url":null,"abstract":"<p><p>Surrogate materials enable pre-treatment prediction of intra-hepatic distribution of therapeutic radioactive microsphere, facilitating patient-specific dosimetry for transarterial radioembolization (TARE). Technetium-99m macroaggregated albumin (⁹⁹ᵐTc-MAA) has long constituted the clinical standard for SPECT-based surrogates, however, its fundamental physicochemical difference from therapeutic microspheres limits the reliability of MAA-based dosimetry and prediction for personalized treatment planning. Next-generation surrogate technology includes biodegradable polymeric microspheres engineered to closely replicate the therapeutic microsphere while affording post-procedural arterial recanalization through controlled biodegradation. Theranostic microspheres incorporating diverse radionuclides, positron-emitting PET compatible surrogates, and multimodal CT and MRI-visible surrogates have collectively expanded same-particle pre-treatment dosimetry capabilities. These material-level advances are synergistically coupled with computational dosimetry tools including artificial intelligence/deep learning algorithms for automated segmentation/dose-prediction, and Monte Carlo simulations that enhance voxel-based dosimetry precision. This review examines recent advances in surrogate materials design and integrated imaging/dosimetry methodologies that enhance TARE efficacy, safety, and personalized treatment outcomes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8580-8610"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PEGylated IL2 and tumor-targeted radiotherapy augment CD8⁺ T cell-mediated anti-tumor response to anti-PD-1 in head and neck squamous cell carcinoma.","authors":"Won Jong Jin, Hari Menon, Amber Bates, Lauren Zebertavage, Yujuan Wang, Paul A Clark, Alexander A Pieper, Caroline P Kerr, Tracy J Berg, Jens C Eickhoff, Sarah Seiter, A Mario Q Marcondes, Mary A Tagliaferri, Willem W Overwijk, Tabassum A Kennedy, Paul M Sondel, Paul M Harari, Justine Y Bruce, Adam R Burr, Reinier Hernandez, Irene M Ong, Jamey Weichert, Zachary S Morris","doi":"10.7150/thno.135255","DOIUrl":"10.7150/thno.135255","url":null,"abstract":"<p><p>Combination of immune checkpoint inhibitors (ICI) with either radiotherapy or PEGylated interleukin 2 (pegIL2) has produced limited or no benefits over ICI alone in clinical trials. A triple combination of radiotherapy, pegIL2, and ICI may overcome the limitations of dual treatments. We report a phase II clinical trial evaluating tumor-targeted radiotherapy, pegIL2 (BEMPEG), and ICI (pembrolizumab) in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), and combination pre-clinically of radiopharmaceutical therapy (RPT), pegIL2, and ICI in HNSCC.</p><p><strong>Methods: </strong>Patients received one cycle of pegIL2 (0.006 mg/kg) plus pembrolizumab (200 mg) followed by external beam radiotherapy (EBRT), then two cycles of pegIL2 plus pembrolizumab. Adverse events, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune response from peripheral blood mononuclear cells (PBMCs) and biopsies were evaluated. RPT (⁹⁰Y-NM600) was evaluated in combination with pegIL2 and anti-PD-L1 in murine MOC2 and SCC7 HNSCC models.</p><p><strong>Results: </strong>We report ORR of 40%, PFS of 4.2 months, OS of 13.6 months, and increased effector:regulatory T-cell ratios and memory CD8⁺ T cells in 5 patients treated prior to trial discontinuation. In preclinical HNSCC models, combined RPT and pegIL2 augmented memory CD8⁺ T cells (IL2Rβ⁺). CD8⁺ T cell depletion led to loss of anti-tumor responses. PegIL2 restored RPT-driven lymphocyte deficiency earlier, increasing memory CD8⁺ T cells (IL2Rβ⁺) in the tumor, and enhanced anti-tumor response through MHC I-dependent TNFα expression. A deficiency of the stimulator of interferon genes (STING) abrogated tumor MHC I expression and antitumor responses. PD-L1-expressing monocytes antagonized CD8⁺ T cell memory effect in the tumor recurrence stage, and anti-PD-L1 therapy promoted ⁹⁰Y-NM600 and pegIL2 efficacy.</p><p><strong>Conclusions: </strong>Preclinically, tumor-targeted RPT and pegIL2 augment response to ICI through CD8⁺ T cell memory acquisition and regulatory monocyte suppression. This study provides preclinical and clinical insight for HNSCC treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8733-8756"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping endometrial vascular functional gradients using depth-derived ultrasound localization microscopy (D-ULM) for early stratification of postinjury fibrotic remodeling and therapeutic guidance.","authors":"Xiaowen Liang, Le Gao, Zhili Guo, Meng Du, Yue Pan, Yixiang Lian, Yu Qiang, Haijun Luo, Ying Zhang, Xiaoyan Kui, Hairong Zheng, Weibao Qiu, Zhiyi Chen","doi":"10.7150/thno.138622","DOIUrl":"10.7150/thno.138622","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Rationale: &lt;/strong&gt;Endometrial injury exhibits significant clinical heterogeneity in fibrotic outcomes. Recovery of microvascular perfusion is central to prognosis, while the depth of injury is an important factor influencing regenerative capacity. However, current clinical imaging techniques are limited by diffraction, resulting in insufficient resolution to reliably depict depth-dependent microvascular architecture of the endometrium, with consequent difficulty in evaluating injury depth or in making early prognostic distinctions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A depth-derived ultrasound localization microscopy (D-ULM) approach is introduced to capture depth-dependent microvascular features in the endometrium. First, we established a normal depth reference band from healthy rats to provide a physiological baseline for identifying pathological vascular changes. Next, in an endometrial injury rat model, we applied unsupervised clustering of early D-ULM features to identify microcirculation phenotypes. Subsequently, we evaluated the correlation between D-ULM features, D-ULM clusters, and late-stage fibrosis area as well as immunofluorescence markers of hypoxia and inflammation, with a view to tying early microvascular changes to eventual recovery or to fibrotic remodeling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In healthy rats, depth-profile curves revealed a distinct transition zone between the deep and superficial layers, enabling the delineation of a quantifiable functional boundary of the endometrial microvasculature. Based on this depth-dependent layering, normal reference intervals were established for the seven D-ULM features. Among these, the reference interval for the vascular distribution center (com_depth_vessel) was 0.371-0.481. In injured cohort, unsupervised hierarchical clustering of day-3 D-ULM features identified three phenotypes: regenerative (Reg), inflammatory hyperperfusion (IH), and irreversible destruction (ID). The day-14 fibrosis area differed significantly among the phenotypes (&lt;i&gt;P&lt;/i&gt; &lt; 0.001), with the Reg phenotype showing the lowest fibrosis, while the IH and ID phenotypes exhibited markedly higher levels. Several D-ULM features were positively correlated with day-14 fibrosis, including com_depth_vessel (ρ = 0.707, q &lt; 0.001), vessel_slope (ρ = 0.539, q = 0.017), vessel_auc (ρ = 0.811, q &lt; 0.001), and mean_vessel_shallow (ρ = 0.846, q &lt; 0.001); conversely, large_ratio_diff was inversely correlated (ρ = -0.568, q = 0.011). The IH phenotype exhibited elevated M1/M2 ratio, HIF-1α, and CD31 expression, whereas the ID phenotype showed increased M1/M2 ratio and HIF-1α but reduced CD31 expression by immunofluorescence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;D-ULM enables depth-resolved imaging of endometrial microvascular functional gradients in a noninvasive manner. This approach provides an imaging framework for early stratification of injury phenotypes, and may guide personalized preventive strategies for patients at ","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8669-8688"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiomyocyte-Specific RNF128 Attenuates Pathological Cardiac Hypertrophy Progression by Stabilizing SERCA2a through Lys63-Linked Polyubiquitination.","authors":"Yujie Zhang, Xuehan Liu, Liwen Yu, Changhao Liu, Jingwei Li, Qingmei Han, Xiaohong Wang, Lei Cao, Liangyu Cai, Linqi Jiao, Guohai Su, Meng Zhang, Cheng Zhang","doi":"10.7150/thno.133221","DOIUrl":"10.7150/thno.133221","url":null,"abstract":"<p><p>Pathological cardiac hypertrophy is maladaptive cardiac remodeling induced by chronic adverse stimuli. In this study, the E3 ubiquitin ligase RNF128 was identified as a suppressor of pathological cardiac dysfunction with therapeutic value.</p><p><strong>Methods: </strong>The expression of Ring Finger protein 128 (RNF128) in pathological cardiac hypertrophy was characterized via public database analysis, scRNA-seq (single-cell RNA sequencing), and further validated in clinical myocardial samples and mouse disease models. The regulatory function of RNF128 in the progression of cardiac hypertrophy was verified <i>in vivo</i> by cardiomyocyte-specific RNF128 knockout mice and cTnT-AAV9-mediated RNF128 overexpression. Ang II (angiotensin II)-stimulated NMCMs (neonatal mouse cardiomyocytes) were used for <i>in vitro</i> validation. Moreover, the downstream target of RNF128 was identified through integrated analysis of scRNA-seq, interactome profiling and quantitative proteomics, followed by a panel of molecular assays.</p><p><strong>Results: </strong>Pathological cardiac hypertrophy reduced RNF128 expression in both human and murine samples. RNF128 deficiency aggravated cardiac dysfunction and pathological remodeling, while its overexpression protected cardiac function. Mechanistically, RNF128 directly interacted with SERCA2a, and catalyzed K63-linked polyubiquitination of SERCA2a at residue K476 (lysine 476), thereby impaired SERCA2a recognition by SQSTM1/p62. Consequently, RNF128 inhibited autophagy-lysosome-mediated degradation of SERCA2a.</p><p><strong>Conclusions: </strong>The findings of this study highlight RNF128 as a novel therapeutic target for heart failure, linking ubiquitination-dependent protein regulation to calcium handling in cardiomyocytes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8689-8707"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Micro/nanorobotics for sepsis diagnosis and therapy: a frontier in precision medicine.","authors":"Yukun Liu, Kang Wang, Guoyun Wan, Fangli Gao, Huiming Tang, Xiangjun Bai, Zhanfei Li, Yuchang Wang","doi":"10.7150/thno.139332","DOIUrl":"10.7150/thno.139332","url":null,"abstract":"<p><p>Sepsis is a serious, life-threatening widespread inflammatory response in the body to infection that can result in multiple organ damage and has a relatively high death rate. Traditional antibiotics and supportive treatments have certain deficiencies, such as poor drug accumulation at the site of infection, delayed identification of pathogens, and an inability to precisely regulate the host immune response. New developments in micro- and nanorobotics have provided new paths for sepsis diagnosis and treatment by means of active motion, intelligent sensing and targeted intervention. Biohybrid microrobots containing DNA nanodevices or enzyme sensors can be used for diagnosis to rapidly detect bacterial pathogens, endotoxins and other markers such as procalcitonin. Motivated micro-robots can overcome the biofilm barrier to deliver drugs and increase the local concentration of antibiotics to inhibit bacterial toxins. Functionalised nanobots of cell membrane or enzyme types can target cytokines, reactive oxygen species and circulating mitochondrial DNA to suppress inflammation and organ damage. The above-mentioned multi-functional platforms have combined pathogen clearance, immune modulation and tissue repair into one treatment. Although the above are promising, there are still some problems in biosafety, propulsion efficiency under complex physiological conditions, large-scale production, and the development of clinically relevant animal models. Future work will focus on building intelligent, biocompatible systems capable of autonomous navigation and adaptation to sepsis. Micro- and nanorobots are generally considered to be a new type of devices for treating sepsis that can achieve targeted and personalised therapy through intelligence.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8757-8774"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}