Theranostics最新文献

{"title":"Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer.","authors":"Fei Peng, Xiaoniao Chen, Lingling Wu, Jiayi He, Zongjin Li, Quan Hong, Qiang Zhao, Meng Qian, Xu Wang, Wanjun Shen, Tingting Qi, Yiyu Huang, Guangyan Cai, Chuyue Zhang, Xiangmei Chen","doi":"10.7150/thno.113741","DOIUrl":"https://doi.org/10.7150/thno.113741","url":null,"abstract":"<p><p><b>Background:</b> The disruption of mitochondrial homeostasis in acute kidney injury (AKI) is an important factor that drives persistent renal dysfunction. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great therapeutic potential in AKI, but insufficient specificity of targeting the impaired mitochondrial function. Herein, we developed an engineered nitric oxide (NO)-primed MSC-EVs (pEVs) to restore mitochondrial homeostasis for AKI therapy. <b>Methods:</b> A cisplatin-induced AKI model was established to investigate the therapeutic effects of MSC-EVs. Proteomic and Western blot analyses compared mitochondrial cargos and functional assays included mitochondrial complex I activity and Adenosine triphosphate (ATP) quantification. Mitochondrial transfer was tracked using flow cytometry and confocal imaging. Mitochondrial dynamics, oxidative stress, and apoptosis were evaluated through ATP measurement, western blotting and rotenone-mediated respiratory chain inhibition. <b>Results:</b> Our data indicated that pEVs outperformed cEVs in restoring renal function and histopathology. Additionally, a reduction in mitochondria-associated oxidative stress and cell death was observed. Proteomic profiling revealed that NO priming enriched pEVs with mitochondrial complex I components, which directly enhanced their bioenergetic capacity, as evidenced by higher mitochondrial complex I activity and elevated ATP production compared to cEVs. In vivo tracking confirmed targeted delivery of pEV-derived mitochondrial contents to renal tubular cells, reducing mitochondrial reactive oxygen species (ROS) and restoring mitochondrial mass. Crucially, mitochondria-depleted pEVs abolished these therapeutic effects, establishing mitochondrial cargos as the primary therapeutic driver. Furthermore, pEVs activated a pro-survival cascade in recipient cells, showing superior efficacy in promoting mitochondrial biogenesis, dynamics, and mitophagy, thereby restoring renal mitochondrial homeostasis. <b>Conclusion:</b> Our study elucidated a mitochondria-targeted therapeutic strategy enabled by engineered EVs that deliver functional cargo to restore mitochondrial homeostasis. These advances provide transformative potential for AKI and other mitochondrial disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5499-5517"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039340","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":"Mechanism of valproic acid-induced hepatic steatosis via enhancing NRF2-FATP2-mediated fatty acid uptake.","authors":"Xiaoliang He, Rui Yuan, Ying Chen, Wenni Huang, Zihao Xu, Bixia Wang, Changhui Liu, Tianqin Xiong","doi":"10.7150/thno.108593","DOIUrl":"https://doi.org/10.7150/thno.108593","url":null,"abstract":"<p><p><b>Rationale:</b> Valproic acid (VPA), a first-line antiepileptic drug, can induce life-threatening hepatic steatosis with prolonged use; however, the underlying mechanisms remain inadequately elucidated. Nuclear factor E2-related factor 2 (NRF2) is a hepatoprotective factor that maintains redox homeostasis; however, increased levels have been observed in VPA-induced hepatic steatosis. Therefore, the present study aimed to investigate the function of NRF2 in VPA-triggered hepatic steatosis. <b>Methods:</b> NRF2 overexpression mice, NRF2 knockout mice, and fatty acid transport protein 2 (FATP2) knockout mice were constructed using adeno-associated virus, homologous recombination, and CRISPR/Cas9 technology, respectively. The mice were then treated with or without oral VPA to induce hepatic steatosis. <b>Results:</b> NRF2 nuclear expression was positively correlated with triglyceride levels in VPA-induced hepatic steatosis. NRF2 overexpression exacerbated VPA-triggered inflammation and steatosis, whereas NRF2 knockout alleviated the effects. Chromatin immunoprecipitation and dual-luciferase reporter gene assay confirmed that FATP2 is a target gene of NRF2. NRF2 exacerbated VPA-induced hepatic steatosis dependent on FATP2. VPA bound to Cys288 and Arg415 of Kelch-like ECH-associated protein 1 (KEAP1), leading to its autophagic degradation and subsequent nuclear translocation of NRF2. <b>Conclusions:</b> Our results revealed a mechanism that VPA binds to specific KEAP1 sites, promoting its degradation and disrupting the KEAP1-NRF2 complex, thereby facilitating NRF2 nuclear translocation. Subsequently, NRF2 activates FATP2 transcription, enhancing fatty acid uptake and contributing to hepatic steatosis. Our findings suggest that inhibiting the NRF2-FATP2 axis could improve VPA-induced hepatic steatosis, offering promising insights into managing drug-induced fatty liver disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5258-5276"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055125","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":"TMTP1-modified nanocarrier boosts cervical cancer immunotherapy by eliciting pyroptosis.","authors":"Hanjie Xu, Danya Zhang, Yu Zhang, Yuxin Chen, Yue Sun, Jie Li, Songwei Tan, Ying Zhou, Rui Wei, Fei Li, Ling Xi","doi":"10.7150/thno.108357","DOIUrl":"https://doi.org/10.7150/thno.108357","url":null,"abstract":"<p><p><b>Rationale:</b> Pyroptosis, an emerging form of programmed cell death, facilitates the release of tumor antigens and inflammatory factors, which can be leveraged to enhance the efficacy of immune checkpoint blockade (ICB) therapy. However, achieving high-efficiency induction of pyroptosis in cancer cells while minimizing toxicity remains a significant challenge. <b>Methods:</b> In this study, we designed a tumor-targeting peptide TMTP1-modified nanostructured lipid carrier (referred to as TP-NLC) with high loading capacities for gambogic acid (GA) and indocyanine green (ICG). The TMTP1, identified by our research team for its tumor-targeting capabilities, was conjugated to the nanocarrier surface using \"click chemistry\" to improve the drug delivery efficiency to tumor tissues. The TP-NLC nanocarrier was thoroughly characterized with respect to its morphological attributes, photostability, tumor-targeting capabilities, ability to induce pyroptosis, reactive oxygen species (ROS)-responsive behavior, and anti-tumor efficacy both <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> GA encapsulated within the TP-NLC nanocarrier, induced pyroptosis in tumor cells, and enhanced the efficacy of ICG-induced pyroptosis under laser irradiation by disrupting intracellular antioxidant systems, realizing that the combination of GA and ICG synergistically induced caspase-3/GSDME-mediated pyroptosis in a ROS-dependent manner. Tumor cells of pyroptosis released cellular contents and tumor antigens, which subsequently promoted the maturation of dendritic cells (DCs), enhanced intratumoral infiltration of CD8⁺ T cells, initiated systemic antitumor immune response, and augmented the efficiency of PD-1 blockade against both primary and metastatic tumors. <b>Conclusion:</b> The combination of GA and ICG therapy utilizing the constructed nanocarriers presents an attractive therapeutic strategy to trigger pyroptosis and potentiate PD-1 blockade therapy for cervical cancer chemo-immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5420-5439"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982915","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":"BARD1-mediated stabilization of METTL14 promotes retinal neovascularization by m6A-modifying MXD1 mRNA on a YTHDF2-dependent manner.","authors":"Xianyang Liu, Shuhao Zeng, Jiayu Meng, Qian Zhou, Fan Cao, Baorui Chu, Chao Wu, Yakun Wang, Hui Feng, Xiaorui Bi, Xinyuan Chen, Wenxian Yang, Meng Tian, Hui Yang, Ke Hu, Shengping Hou","doi":"10.7150/thno.110122","DOIUrl":"https://doi.org/10.7150/thno.110122","url":null,"abstract":"<p><p>Retinal vascular diseases are typified by the proliferation of irregular and leaky microvessels, resulting in vision impairment. Although the etiology of retinal angiogenesis is not yet fully understood, it is evident that microglia play a pivotal role in promoting angiogenesis. <b>Methods:</b> In vivo, the METTL14 conditional knockout (cKO) mouse was constructed to investigate the role of METTL14 in oxygen-induced retinopathy (OIR). In vitro, a combination of methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-sequencing (RNA-seq), RNA Immunoprecipitation (RIP) assay, dual-luciferase reporter assays, and Chromatin immunoprecipitation-qPCR (ChIP-qPCR), was performed to explore the underlying mechanisms. <b>Results:</b> The proteomic analysis of hypoxic microglia has uncovered a pronounced enrichment in pathways related to RNA modification. Western blot has revealed that N6-methyladenosine (m6A) methyltransferase-like 14 (METTL14) exhibits the most significant increase among the RNA methylases. METTL14 cKO mice within an OIR model showed fewer neovascular formations. Additionally, in co-culture with sh-METTL14 HMC3 cells, HRMECs also exhibited reduced angiogenesis capabilities. Mechanically, E3 ubiquitin-protein ligase BARD1 can directly interact with METTL14, leading to an up-regulation of METTL14 protein level in hypoxic microglia. METTL14 could directly modifies and regulates the transcription factor MAX Dimerization Protein 1 (MXD1), which is subsequently recognized by the m6A \"reader\" YTH domain-containing family protein 2 (YTHDF2). Consequently, the modified MXD1 modulates the expression of VEGFA and VCAM1, promotes retinal neovascularization. <b>Conclusion:</b> Our study highlights the critical role of METTL14 in the OIR model and suggests a novel therapeutic target for addressing retinal vascular diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5481-5498"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019793","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":"Old players and new insights: unraveling the role of RNA-binding proteins in brain tumors.","authors":"Xu Wang, Jiang Li, Chengkai Zhang, Xiudong Guan, Xingang Li, Wang Jia, Anjing Chen","doi":"10.7150/thno.113312","DOIUrl":"https://doi.org/10.7150/thno.113312","url":null,"abstract":"<p><p>The human genome harbors >1,600 evolutionarily conserved RNA-binding proteins (RBPs), with extensive multi-omics investigations documenting their pervasive dysregulation in malignancies ranging from glioblastoma to melanoma. These RBPs are integral to the complex regulatory networks governing hallmark cancer processes. Recent studies have investigated the multifaceted contributions of RBPs to tumorigenesis, tumor metabolism, the tumor-immune microenvironment, and resistance to therapy. This complexity is further compounded by the intricate regulation of RNA function at various levels by RBPs, as well as the post-translational modifications of RBPs, which improve their functional capacity. Moreover, numerous RBP-based therapeutics have emerged, each underpinned by distinct molecular mechanisms that extend from genomic analysis to the interference of RBPs' function. This review aims to provide a comprehensive overview of the recent progress in the meticulous roles of RBPs in brain tumors and to explore potential therapeutic interventions targeting these RBPs, complemented by a discussion of innovative techniques emerging in this research field. Advances in deciphering RNA-RBP interactomes and refining targeted therapeutic strategies are revealing the transformative potential of RBP-centric approaches in brain tumor treatment, establishing them as pivotal agents for overcoming current clinical challenges.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5238-5257"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062308","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":"Single-nucleus RNA sequencing and spatial transcriptomics reveal an immunosuppressive tumor microenvironment related to metastatic dissemination during pancreatic cancer liver metastasis.","authors":"Hongsen Liu, Mengting Chen, Bo Hong, Yufei Xiao, Qianming Chen, Yun Qian","doi":"10.7150/thno.108925","DOIUrl":"https://doi.org/10.7150/thno.108925","url":null,"abstract":"<p><p><b>Background:</b> Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by early liver metastasis and high mortality. The tumor microenvironment plays a pivotal role in tumor progression; however, the immune microenvironment's involvement in PDAC liver metastasis remains poorly understood. <b>Methods:</b> This study investigates cellular heterogeneity in primary tumor (PT) and liver metastasis (LM) tissues of PDAC using single-nucleus RNA sequencing and spatial transcriptomics. Intra-tumor heterogeneity and cell interactions were elucidated through deconvolution, intercellular signalling, pseudotime analysis, and immune infiltration profiling. The spatial distribution of immune cells was assessed by multiplexed immunofluorescence staining, and prognostic models were developed and validated through immunohistochemistry (IHC). Analyzing the regulatory role of CITED4 in the invasion and metastasis of pancreatic cancer cells through transwell assay and scratch wound healing assay. <b>Results:</b> A total of 62,326 cells were sequenced, with metastatic dissemination cells showing significant upregulation of epithelial-mesenchymal transition (EMT)-related genes during liver metastasis. Spatial transcriptomics revealed the enrichment of metastatic dissemination cells and FOXP3-related T_reg cells at the tumor front in PT tissues. In comparison to LM tissues, the tumor front in PT tissues fosters an immunosuppressive microenvironment through the accumulation of T_reg cells. Interaction analysis identified the SPP1 pathway as a key promoter of this immunosuppressive environment. Furthermore, prognostic models highlighted CITED4 as critical biomarkers in PDAC. Elevated CITED4 expression is correlated with liver metastasis and poor prognosis in patients with PDAC. siRNA-mediated knockdown of CITED4 suppresses the invasion and metastasis of pancreatic cancer cells. <b>Conclusions:</b> In summary, this study revealed that T_reg cell alterations, mediated by metastatic dissemination cells within the immune microenvironment, significantly contribute to PDAC liver metastasis, and that CITED4 enhances the metastatic potential of metastatic dissemination cells.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5337-5357"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055126","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 drug delivery systems for advanced immune checkpoint blockade therapy.","authors":"Chenqi Guo, Ling Lin, Yihan Wang, Jing Jing, Qiyong Gong, Kui Luo","doi":"10.7150/thno.112475","DOIUrl":"https://doi.org/10.7150/thno.112475","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have been widely utilized in the first-line therapy of various types of cancer. However, immune-related adverse events (irAEs) and resistance to ICIs remain intractable challenges for immune checkpoint blockade (ICB) therapy during clinic treatment. Nano drug delivery systems (NDDSs) have shown promising potential to improve anticancer efficacy and reduce side effects of small molecular drugs. The combination of nanotechnology and ICB provides new opportunities to overcome the challenges of immunotherapy. Nanoplatforms have been employed for direct delivery of ICIs, and they are preferred vehicles for combination therapy of ICIs and other therapeutic agents. In this review, the strategies of using NDDSs for advancing ICB therapy in recent years are surveyed, emphasizing the employment of NDDSs for combination treatment by ICIs and other agents to manipulate antitumor immunity. Analysis of current strategies for applying NDDSs for ICB leads to future research directions and development trends.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5440-5480"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035755","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":"Bispecific Siglec-15/T cell antibody (STAB) activates T cells and suppresses pancreatic ductal adenocarcinoma and non-small cell lung tumors <i>in vivo</i>.","authors":"Limei Shen, Alison Schaefer, Justin Huckaby, Whitney Wolf, Samuel K Lai","doi":"10.7150/thno.103372","DOIUrl":"10.7150/thno.103372","url":null,"abstract":"<p><p><b>Rationale:</b> Siglec-15 (S15) is a membrane-associated antigen overexpressed across various cancer types, and also induces immunosuppression. We believe this makes S15 a promising target for cellular immunotherapy of solid tumors characterized by an immunosuppressive tumor microenvironment, but this remains underexplored to date. <b>Method:</b> We engineered a bispecific antibody that simultaneously binds S15 on tumor cells and CD3 on T cells in the popular IgG-scFv format; we termed this molecule STAB. <b>Results:</b> <i>In vitro</i>, STAB induced marked proliferation of CD3+ T cells in human PBMCs, and mediated effective killing of Panc-1 pancreatic ductal adenocarcinoma (PDAC) and H460 non-small cell lung cancer (NSCLC) cells in co-culture studies with PBMCs or CD3+ T cells. In NSG mice with human PDAC and NSCLC tumors, STAB effectively suppressed tumor growth and prolonged survival, in sharp contrast to mice receiving either anti-S15 or anti-CD3 mAbs alone. STAB increased activated T cells in both tumor and circulation, as well as reduced the stromal barrier-a key hallmark of PDAC. <b>Conclusion:</b> Our results underscore STAb as a promising therapeutic molecule to be investigated further for PDAC and NSCLC, and potentially other S15-positive solid tumors.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5529-5542"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013955","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":"Pilot first-in-human CCR2 PET/CT to detect abdominal aortic aneurysm wall instability.","authors":"Santiago Elizondo-Benedetto, Deborah Sultan, Ryan Wahidi, Mahdjoub Hamdi, Mohamed S Zaghloul, Shahab Hafezi, Batool Arif, Laura K McDonald, Kitty Harrison, Dakkota Thies, Gyu Seong Heo, Hannah Luehmann, Lisa Detering, J Westley Ohman, Zachary J Wanken, Luis A Sanchez, Joseph E Ippolito, Jie Zheng, Robert J Gropler, Richard Laforest, Yongjian Liu, Mohamed A Zayed","doi":"10.7150/thno.108656","DOIUrl":"10.7150/thno.108656","url":null,"abstract":"<p><p><b>Objective:</b> In a pilot first-in-human study, we aimed to evaluate the feasibility of Positron Emission Tomography/Computed Tomography (PET/CT) imaging of C-C chemokine receptor type 2 (CCR2) to aid in the diagnosis of abdominal aortic aneurysm (AAA) instability. <b>Rationale:</b> Risk stratification of AAAs is an unmet clinical need. Patients often remain asymptomatic until they acutely rupture. Current imaging techniques focus on AAA diameter and growth rate, neglecting key cellular and molecular processes. <b>Methods:</b> A pilot, prospective, single-center, case-control study evaluated patients with and without AAAs. The study subjects received intravenous administration of a CCR2-specific radiotracer, followed by PET/CT assessment. Surgical AAA specimens were collected to evaluate CCR2 content and extracellular matrix integrity. PET/CT signals were evaluated in the AAA wall in the para-renal, mid-infrarenal, and aneurysm sac, and analyzed relative to patient demographics, AAA anatomical segmentation, and wall rupture potential index (RPI). <b>Results:</b> The AAA group was elderly (70.7 ± 7.3), with an aneurysm diameter of 4.86 ± 0.75 cm, and a higher prevalence of hyperlipidemia and statin use. Regardless of the anatomical segment analyzed, AAA surgical patients demonstrated a higher CCR2 radiotracer signal in the aortic tissue than others. However, no correlation was observed between the radiotracer signal and the AAA diameter. Patients with a higher radiotracer signal, particularly in the AAA posterior wall of the maximum-diameter region, were significantly correlated with RPI (P = 0.03). Histomorphic analysis demonstrated significantly elevated CCR2 levels, along with increased macrophage infiltration, matrix metalloproteinase activity, and severe elastin degradation. <b>Conclusions:</b> This first-in-human study demonstrated that CCR2 PET/CT molecular imaging is feasible and can identify increased wall instability in individuals with AAAs, especially in those at higher risk of disease progression.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5518-5528"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033202","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":"Shh agonist enhances maturation in homotypic Lgr5-positive inner ear organoids.","authors":"Nathaniel T Carpena, So-Young Chang, Seyoung Mun, Kyung Wook Kim, Hyun C Yoon, Phil-Sang Chung, Ji-Hun Mo, Jin-Chul Ahn, Ji On Park, Kyudong Han, Ji Eun Choi, Jae Yun Jung, Min Young Lee","doi":"10.7150/thno.107345","DOIUrl":"10.7150/thno.107345","url":null,"abstract":"<p><p><b>Background:</b> The regeneration of functional hair cells (HCs) remains a critical challenge in addressing sensorineural hearing loss. This study aimed to investigate the molecular and functional mechanisms driving stereocilia maturation within inner ear organoids (IEO) derived from homogenic Lgr5-positive progenitor cells (LPCs) and to compare outcomes with traditional heterotypic cultures. <b>Methods:</b> Mouse cochlear LPCs were isolated via magnetic-activated cell sorting (MACS) to establish homotypic cultures, ensuring purity and eliminating the heterotypic influences present in traditional manual isolation (MI) methods. Differentiation into HCs was induced through Wnt and Notch signaling modulation. Transcriptomic profiling using bulk and single-cell RNA sequencing (scRNA-seq) identified gene expression changes linked to stereocilia development. A Sonic Hedgehog (Shh) agonist was applied to enhance structural maturation of HCs. Functional assessment included electron microscopy, FM1-43 uptake assays, and microelectrode array recordings in assembloids of IEO with primary spiral ganglion neurons (SGN) co-cultures. <b>Results:</b> While homotypic LPC-derived IEOs successfully differentiated into HC-like cells, initial morphological assessment revealed immature stereocilia structures. Bulk RNA-seq analysis highlighted a downregulation of morphogenesis-related genes in these organoids. The application of a Shh agonist, acting as a key morphogen, promoted stereocilia development, as evidenced by enhanced ultrastructural features and increased expression of cuticular plate-associated genes (<i>Pls1, Lmo7</i> and <i>Lrba)</i>. Single-cell RNA sequencing (scRNA-seq) further identified distinct cell clusters, which exhibited robust expression of stereocilia-related genes (<i>Espn, Lhfpl5, Loxhd1</i> and <i>Tmc1)</i>, indicative of advanced HC maturation. Electrophysiological assessments of IEO-SGN assembloids using microelectrode arrays confirmed functional mechanoelectrical transduction between cells. <b>Conclusion:</b> This integrated approach elucidates critical pathways and cellular dynamics underpinning stereocilia maturation and functional HC development in EIOs. These findings provide new insights into the molecular regulation of HC maturation and support the utility of Shh-modulated IEOs as a promising platform for inner ear regeneration and therapeutic development for inner ear regenerative therapies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5543-5565"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035763","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}