Theranostics最新文献

{"title":"Ultrasound spatiotemporally enables prolonged therapeutic mRNA translation in engineered bacteria for enhanced cancer immunotherapy.","authors":"Zhaoyou Liu, Lantian Wang, Jieyuan An, Tian Zhou, Mengying Wei, Guodong Yang, Pengying Wu, Lijun Yuan","doi":"10.7150/thno.120342","DOIUrl":"https://doi.org/10.7150/thno.120342","url":null,"abstract":"<p><p><b>Rationale:</b> Engineered bacteria have recently emerged as a novel and promising strategy for cancer immunotherapy. Nonetheless, precise spatiotemporal regulation of therapeutic gene expression within these bacteria is essential to optimize therapeutic efficacy while minimizing adverse effects. This study aims to develop a system for precise, ultrasound-driven regulation of gene expression in bacteria to enable targeted tumor therapy. <b>Methods:</b> A modular system (Stabilized Open RNA thermometer, SORT) was designed, comprising a modified RNA thermometer with QKI response elements (QRE), therapeutic coding sequences, and the RNA binding motif of QKI. As a proof-of-concept, the bacteria VNP20009 was engineered with plasmids expressing mutated IL-2 or soluble PD-1 (sPD-1) within the SORT cassette. Syngeneic tumor mouse models (4T1 breast cancer and A20 lymphoma) were used to assess bacterial accumulation, therapeutic protein expression, anti-tumor immunity, and toxicity. <b>Results:</b> Upon a single session of ultrasound irradiation, IL-2 or sPD-1 expression was efficiently and durably induced in the engineered VNP20009. In mouse tumor models, SORT-equipped VNP20009 accumulated in the tumor region and diminished from organs including the liver and lung. Ultrasound irradiation enabled the therapeutic protein (IL-2 or sPD-1) to be spatiotemporally switched-on within the tumor region. This localized expression resulted in robust activation of anti-tumor immunity alongside tolerable toxic effects. <b>Conclusions:</b> The modular SORT platform provides a refined approach for bacteria-based therapy, enabling spatiotemporal control of therapeutic gene expression. This system enhances anti-tumor efficacy while reducing off-target toxicity, representing a promising strategy for cancer immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9742-9756"},"PeriodicalIF":13.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213715","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":"GPX1-driven selenium nanoplatform reprograms MAMs-mediated organelle crosstalk to reverse inflammatory adipose expansion in thyroid eye disease.","authors":"Yao Tan, Feng Zhang, Jiamin Cao, Lemeng Feng, Bingyu Xie, Limo Gao, Xiangdong Chen, Zuyun Yan, Wei Xiong","doi":"10.7150/thno.117582","DOIUrl":"https://doi.org/10.7150/thno.117582","url":null,"abstract":"<p><p><b>Background:</b> Thyroid eye disease (TED) is a multifactorial autoimmune disorder with limited therapeutic options due to the complexity of its oxidative, metabolic, and inflammatory networks. This study aims to develop a selenium-based nanoplatform that targets mitochondria-ER interactions to reverse inflammatory adipose expansion in TED. <b>Methods:</b> We designed a dual-responsive selenium nanoparticle (Se@LNT) modified with lentinan, capable of ROS/pH-triggered release. Human primary orbital fibroblasts, bioinformatic analysis of public datasets, and TED mouse models were used to investigate the therapeutic mechanism. <b>Results:</b> Se@LNT undergoes intracellular metabolic conversion into selenocysteine, which enhances GPX1 activity and promotes redox balance. It exerts triple regulatory effects by stabilizing mitochondrial membranes to reduce mtDNA leakage, downregulating GRP75 to normalize MAMs contact and calcium flux, and suppressing PERK-eIF2α-ATF4 signaling to relieve ER stress. Transcriptomic profiling reveals multi-target modulation of immune-stromal interactions. <i>In vivo</i>, Se@LNT achieves orbital targeting, rapid hepatic-renal clearance, and significant reduction of adipose expansion with immune remodeling. <b>Conclusions:</b> Se@LNT offers the first MAMs-targeted nanotherapy for TED by reprogramming organelle crosstalk, restoring metabolic-immune homeostasis, and modifying disease progression at the subcellular level.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9601-9622"},"PeriodicalIF":13.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213746","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":"Dual-parameter tomographic imaging of attenuation and backscattering coefficients for quantitative evaluation of immune cell-mediated cytotoxicity in tumor spheroids.","authors":"Seokgyu Han, Ingyoung Kim, Baekcheon Seong, Woovin Kim, Hongseong Kim, Sein Kim, Chulmin Joo, Sungsu Park","doi":"10.7150/thno.118722","DOIUrl":"https://doi.org/10.7150/thno.118722","url":null,"abstract":"<p><p><b>Rationale:</b> Quantitative, non-perturbative assessment of immune cell-mediated cytotoxicity in tumor spheroids remains challenging due to the lack of real-time label-free analytical tools. Conventional methods such as fluorescence imaging or biochemical assays often require labeling and provide limited longitudinal analysis, which prohibits dynamic monitoring of therapeutic responses. This study presents a dual-parameter tomographic analysis method that simultaneously quantifies attenuation coefficient (AC) and backscattering coefficient (BSC) from optical coherence tomography (OCT) datasets, enabling dynamic evaluation of therapeutic responses in three-dimensional (3D) tumor spheroids. <b>Methods:</b> We developed a 3D Gabor transform-based algorithm to extract depth-resolved AC and BSC metrics from OCT volumetric datasets. Unlike conventional strategies, our method enables simultaneous voxel-wise measurements of AC and BSC values, with superior noise robustness. Experiments with intralipid solutions across a range of concentrations revealed that the Gabor-based approach yielded AC and BSC estimations with more than three times greater precision than prior methods. This approach enables high-resolution measurements of structural and optical property changes associated with apoptosis, allowing spatial and temporal mapping of treatment-induced cytotoxicity in HER2-positive breast tumor spheroids treated with AZD4547 and HER2-targeted chimeric antigen receptor (CAR) T cells. <b>Results:</b> In AZD4547-treated spheroids, AC increased dose-dependently from 0.39 to 0.64, reflecting a 64% rise, while BSC increased from 0.09 to 0.12, an approximate 33% increase. CAR T cell treatment induced a rapid, spatially progressive increase in both AC and BSC, originating at the spheroid periphery and advancing inward. Over 12 hours, AC rose from 0.40 to 0.82 (2-fold increase) and BSC from 0.09 to 0.20 (2.2-fold increase). While AC and BSC individually correlated with spheroid viability, their combined analysis consistently achieved a higher coefficient of determination (R² = 0.98) across both treatment modalities. <b>Conclusions:</b> This dual-parameter OCT-based assay framework provides a sensitive, label-free method for distinguishing between immune- and drug-induced apoptosis in tumor spheroids. Its strong correlation with viability and capacity to resolve spatially resolved dynamics underscore its potential for robust, <i>in situ</i> assessment of immunotherapeutic efficacy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9399-9414"},"PeriodicalIF":13.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213766","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":"Trimmed <i>N</i>-glycans define aggressive gastric cancer and predict clinical outcomes.","authors":"Dylan Ferreira, Beatriz Marinho-Santos, Marta Relvas-Santos, Bernardo Orr, Andreia Brandão, Luís Pedro Afonso, Lúcio Lara Santos, José Alexandre Ferreira","doi":"10.7150/thno.111670","DOIUrl":"https://doi.org/10.7150/thno.111670","url":null,"abstract":"<p><p><b>Rationale:</b> Gastric cancer (GC) is a leading cause of cancer-related mortality, particularly in advanced stages where prognosis and targeted treatment remain challenging. The glycocalyx, a dense network of glycans and glycoproteins, is critical for tumor progression and immune evasion, yet its molecular signatures are poorly understood. This study investigates glycan-based biomarkers of aggressiveness, focusing on paucimannosidic <i>N</i>-glycans, a previously underexplored glycosylation pattern in cancer. <b>Methods:</b> High-throughput <i>N</i>-glycome analysis was performed on gastric tumors of varying aggressiveness, followed by <i>Galanthus Nivalis</i> Lectin (GNL) immunostaining to assess paucimannosidic glycans across tumor stages. Comparative analysis was performed against clinically relevant GC biomarkers (E-cadherin, p53, MSI, sTn, sLeA). TCGA analysis correlated key paucimannose-associated glycosyltransferases with clinical outcomes. Glycoproteomics identified glycoproteins carrying paucimannoses, later validated using immunoassays in tumor tissues for clinical relevance. Additionally, serum samples were analyzed to evaluate the non-invasive potential of GNL reactivity and associated glycoproteins. <b>Results:</b> Aggressive gastric tumors were significantly enriched in paucimannosidic <i>N</i>-glycans, a feature not previously reported in this malignancy. Lectin immunoblotting confirmed their disease specificity, with expression increasing with tumor progression. GNL staining outperformed established biomarkers in prognostic accuracy. TCGA analysis of more than 400 cases showed a strong correlation between high paucimannose-associated glycosyltransferase expression and poor prognosis. Glycoproteomics unexpectedly revealed paucimannose <i>N</i>-glycans primarily on intracellular ribosomal proteins, though key membrane proteins like MMP9 displayed aberrant paucimannosylation. MMP9 expression increased with tumor stage and grade, with tumors co-expressing MMP9 and paucimannosidic glycans exhibiting the worst prognosis. In serum, only MMP9 demonstrated diagnostic potential as a circulating biomarker, whereas GNL did not show a significant association. <b>Conclusions:</b> This study provides the first comprehensive characterization of the GC glycome, linking paucimannosidic <i>N</i>-glycans to tumor aggressiveness and poor clinical outcome. These glycans demonstrated superior prognostic performance compared to established clinical biomarkers. Their association with MMP9 further suggests a key role in disease progression. Together, these findings suggest that alterations in <i>N</i>-glycosylation, including paucimannosylated glycoproteins, hold promise for future prognostic and therapeutic applications in gastric cancer.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9375-9398"},"PeriodicalIF":13.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213743","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":"Quantitative MALDI imaging of aspirin metabolites in mouse models of triple-negative breast cancer.","authors":"Tae-Hun Hahm, Dalton R Brown, Caitlin M Tressler, Thao Tran, Alice Ly, Arvind P Pathak, Michael T McMahon, Kristine Glunde","doi":"10.7150/thno.116819","DOIUrl":"https://doi.org/10.7150/thno.116819","url":null,"abstract":"<p><p><b>Rationale:</b> The non-steroidal anti-inflammatory drug aspirin is currently being developed as activatable contrast agent for chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI), for detection of its CEST MRI active metabolite salicylic acid (SA). This study refines and develops quantitative matrix-assisted laser desorption/ionization (QMALDI) imaging to investigate the distribution of aspirin metabolites including SA in triple-negative breast cancer (TNBC) models in mice. <b>Method:</b> In this study, we established QMALDI imaging with norharmane (nH) matrix and assisted by the addition of 5 mM peracetic acid (PAA) for optimized SA detection. Deuterated D₆-SA was added as an internal standard to quantify SA detection. PAA was applied via spraying to improve matrix uniformity and reduce crystal size by forming hydrogen bonds with the nH matrix. Ultraviolet (UV) irradiation during MALDI imaging activated PAA, generating reactive radicals that facilitated the breakdown of nH matrix compounds, thereby reducing matrix-related noise. <b>Results:</b> QMALDI imaging with 5 mM PAA-doped nH matrix and D₆-SA as internal standard revealed SA accumulation of 141.9 ± 22.6 pmol/mm² in the liver, 129.5 ± 7.8 pmol/mm² in the kidney, and 50.4 ± 3.0 pmol/mm² in TNBC tumors following intravenous injection of aspirin in mice. Precise spatial alignment, integration, and quantification of MALDI imaging, histology, and immunofluorescence images from CD31 staining for blood vessels allowed us to accurately evaluate the spatial distribution of SA in tissue regions enriched with blood vessels and in specific anatomical regions. This spatial data analysis revealed high SA accumulation in the kidney medulla, viable tumor rim containing CD31-stained blood vessels, and throughout the liver. <b>Conclusion:</b> This newly developed QMALDI imaging approach for detecting aspirin metabolites demonstrated high SA accumulation in the kidney medulla and tumor rim containing blood vessels within viable tumor regions following systemic aspirin injection in mice, consistent with our previous study using aspirin-generated SA as activated contrast agent for CEST MRI. This approach enhances the spatial and tissue structural accuracy of quantitative analysis, reinforcing the potential of QMALDI imaging for investigating contrast agents, drug distributions, and metabolism in various tissues.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9359-9374"},"PeriodicalIF":13.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213594","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":"Alisol A ameliorates vascular cognitive impairment via AMPK/NAMPT/SIRT1-mediated regulation of cholesterol and autophagy.","authors":"Ping Xu, Wen Zhou, Shida Wang, Linjiao Wang, Yu Bai, Shan Xing, Wenda Xue, Meng Li, Jun Shi, Haoxin Wu","doi":"10.7150/thno.112661","DOIUrl":"https://doi.org/10.7150/thno.112661","url":null,"abstract":"<p><p>Atherosclerosis-related vascular cognitive impairment (VCI) is associated with dysregulated cholesterol metabolism and impaired autophagy. Alisol A, a natural tetracyclic triterpenoid derived from the traditional ZeXieYin Formula, has demonstrated anti-atherosclerotic and neuroprotective effects. However, its role in modulating brain cholesterol homeostasis and mitophagy in VCI remains largely unexplored. <b>Methods:</b> To elucidate the mechanism of Alisol A and evaluate its translational relevance, we employed an <i>Ldlr^-/-</i> mouse model of VCI induced by a high-fat diet and left common carotid artery ligation. Alisol A was administered intragastrically, and cognitive function was assessed using the Morris water maze, Y-maze, and novel object recognition tests. To probe the role of NAMPT, pharmacological inhibition and lentiviral overexpression strategies were applied. Mechanistic investigations included Western blotting, immunofluorescence, and transmission electron microscopy to examine cholesterol metabolism, oxidative stress, mitophagy, and synaptic plasticity. Additionally, molecular docking, surface plasmon resonance, and lipidomic profiling were used to explore Alisol A-NAMPT binding and downstream regulatory pathways. <b>Results:</b> Alisol A significantly ameliorated cognitive impairment in <i>Ldlr^-/-</i> mice. Mechanistically, it restored cholesterol homeostasis by activating the AMPK/NAMPT/SIRT1 signaling axis, upregulated UCP2 to suppress oxidative stress, and inhibited glial activation, thereby preserving neuronal structure and function. Additionally, Alisol A reactivated mitophagic flux by enhancing PINK1/PARKIN signaling and facilitating the clearance of damaged mitochondria, ultimately improving mitochondrial function. NAMPT was identified as a key molecular target mediating these neuroprotective effects. <b>Conclusion:</b> Alisol A confers neuroprotection in VCI by regulating cholesterol metabolism, attenuating oxidative stress, and restoring mitophagy via NAMPT-mediated signaling. These findings highlight its therapeutic potential in atherosclerosis-related cognitive decline.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9415-9446"},"PeriodicalIF":13.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213592","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 contrasting regulatory effects of valproic acid on ferroptosis and disulfidptosis in hepatocellular carcinoma.","authors":"Rongrong Liu, Xinyan Li, Jiayi Xu, Liangwen Yan, Kailing Hu, Mengjiao Shi, Yinggang Zhang, Yaping Zhao, Yudan Fan, Gang Wang, Ying Guo, Yetong Feng, Pengfei Liu","doi":"10.7150/thno.115661","DOIUrl":"10.7150/thno.115661","url":null,"abstract":"<p><p><b>Background</b>: Valproic acid (VPA), a branched short-chain fatty acid, is extensively utilized as both an antiepileptic medication and a mood stabilizer. However, the complete pharmacological functions of VPA on programmed cell death are still not fully understood. In this study, we investigated the role of VPA in modulating ferroptosis and disulfidptosis, which are emerging forms of programmed cell death triggered by lipid peroxidation and disulfide stress respectively. <b>Methods</b>: Herein, the network pharmacology analysis, genome-wide mRNA transcription assay and metabolomics analysis were performed to predict the major pharmacological action and potential targets of VPA. To confirm the hypothesis, pharmacological targeting model and gene knockdown model was created in our work. The pharmacological action of VPA on ferroptosis and disulfidptosis was evaluated respectively. <b>Results</b>: Our findings primarily indicated that the potential targets of VPA were linked to hepatocarcinogenesis and programmed cell death. Additionally, omics data suggested that VPA could significantly influence iron transport and glucose homeostasis. Notably, VPA heightened the susceptibility of hepatocellular carcinoma (HCC) cells to ferroptosis by increasing the labile iron pool, facilitating the accumulation of free iron through enhanced cellular ferritinophagy and reduced ferritin expression. Furthermore, VPA promoted the transcription of glucose-6-phosphate dehydrogenase (G6PD) and impacted glutathione (GSH) metabolism. The activation of the NRF2-G6PD pathway induced by VPA further augmented the production of NADPH and GSH, which subsequently inhibited the formation of disulfide bonds among various cytoskeletal proteins, as well as disulfidptosis in HCC cells. <b>Conclusion</b>: Overall, our results highlight the significant role of VPA in differentially regulating ferroptosis and disulfidptosis in HCC cells, thereby offering a precise avenue for addressing drug-resistant HCC in clinical practice.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9091-9113"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081681","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":"Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury.","authors":"Jinchao Wang, Lei Li, Jianye Xu, Dilmurat Gheyret, Kaiji Li, Xu Zhang, Haoran Jia, Ye Tian, Xiao Liu, Shenghui Li, Guili Yang, Yalong Gao, Ruilong Peng, Huajie Liu, Bin Liu, Jianfeng Zhuang, Cong Wang, Xin Chen, Yafan Liu, Bo Chen, Chuan Huang, Yuhan Li, Xin Chen, Jianning Zhang, Shu Zhang","doi":"10.7150/thno.115746","DOIUrl":"10.7150/thno.115746","url":null,"abstract":"<p><p>Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. <b>Methods:</b> We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating <i>in vivo</i> multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4^-/-, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. <b>Results:</b> Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. <b>Conclusions:</b> These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9221-9239"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081691","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":"Reprogramming the aging ovarian microenvironment via mitochondrial sharing and structural remodeling.","authors":"Chia-Jung Li, Li-Te Lin, Pei-Hsuan Lin, Jim Jinn-Chyuan Sheu, Zhi-Hong Wen, Kuan-Hao Tsui","doi":"10.7150/thno.119957","DOIUrl":"10.7150/thno.119957","url":null,"abstract":"<p><p><b>Rationale:</b> Mitochondrial dysfunction in ovarian granulosa cells (GCs) and cumulus cells (CCs) is a defining feature of reproductive aging, contributing to impaired oocyte quality and reduced fertility. This study investigates whether enhancing cytoskeletal dynamics or promoting structural contact between cells can restore mitochondrial function and mitigate ovarian aging. <b>Methods:</b> Mitochondrial exchange was assessed using co-culture systems, live-cell imaging, and mitochondrial labeling in human ovarian somatic cells. Cytoskeletal modulation was achieved using FTY720, and cell-cell contact was enhanced through soft 3D extracellular matrix (ECM) scaffolds. Functional outcomes were evaluated through ATP assays, mitochondrial membrane potential, Seahorse bioenergetics profiling, and transcriptomic analysis. In vivo validation was conducted in aged mice treated with FTY720. <b>Results:</b> Granulosa and cumulus cells exchanged mitochondria via tunneling nanotubes (TNTs), a process significantly reduced with age. Mitochondrial transfer was contact-dependent and not mediated by paracrine signaling. FTY720 enhanced TNT formation and mitochondrial delivery, restoring ATP levels, membrane potential, and oxidative phosphorylation in aged cells. 3D ECM culture promoted spheroid formation, activated YAP signaling, and improved mitochondrial function without pharmacological agents. In aged mice, FTY720 treatment increased follicle numbers, improved oocyte mitochondrial quality, and elevated serum AMH levels. <b>Conclusions:</b> These findings demonstrate that somatic cell contact is essential for mitochondrial complementation in aging ovaries. By promoting intercellular connectivity through cytoskeletal or microenvironmental remodeling, endogenous mitochondrial sharing can be reactivated to restore bioenergetic function. This approach offers a novel regenerative strategy to counteract reproductive aging.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9279-9293"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081733","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":"Designer amphiphilic helical peptide-decorated nanomicelles enable simultaneous inflammation control and triple-destruction of bacteria for treating bacterial pneumonia and sepsis.","authors":"Sixia Liu, Rui Wang, Lian Li, Xiaohuan Wang, Jiameng Gong, Xingzu Liu, Zichen Song, Liya Sun, Xiali Liu, Wen Ning, Yuanlin Song, Shan-Yu Fung, Hong Yang","doi":"10.7150/thno.110538","DOIUrl":"10.7150/thno.110538","url":null,"abstract":"<p><p>Multifunctional nanodevices that simultaneously destruct bacteria and control detrimental inflammation are anticipated to serve as an effective therapy for sepsis. Toll-like receptor 2 (TLR2) and TLR4 signaling pathways are pivotal to the pathogenesis of sepsis from the clinical data analysis. Herein, inspired by understanding of the molecular interactions between TLR2/4 and their natural ligands, we <i>de novo</i> design an amphiphilic, helical, cationic peptide R18, which potently inhibits the activation of both TLR2 and TLR4, and eradicates bacteria. Such inhibition is primarily achieved by binding of R18 to TLR2 or to both TLR4 ligand and receptor, which interferes with the ligand-receptor interactions. We also define the essential role of the hydrophobic and cationic amino acid residues in the peptide sequence in these multi-actions. By conjugating R18 to the self-assembled PEGylated phospholipid-based nanomicelles (designated as M-CR18), the antibacterial activity and the stability are significantly enhanced. The mechanistic studies reveal that M-CR18 effectively eliminates bacteria through triple-destruction on bacterial membrane integrity, biofilm formation, and bacterial flagellar assembly when compared with the molecular R18. The <i>in vivo</i> efficacy of M-CR18 is validated in infectious mouse models of cecal ligation and puncture as well as <i>Pseudomonas aeruginosa</i>-induced acute lung injury, and a non-infectious mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation. Finally, M-CR18 can effectively eliminate clinically present drug-resistant bacteria. This study provides a <i>de novo</i> design principle for multifunctional nanodevices with immunomodulatory and antibacterial activities, which represent a novel class of nano-antibiotics for the treatment of bacterial infection-mediated pneumonia and sepsis.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9047-9072"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081580","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}