Theranostics最新文献

{"title":"Esterase-responsive albumin-binding PROTAC-mediated BRD4 degradation for cancer immunotherapy.","authors":"Hoyeon Lee, Sojin Jeong, Juwon Park, Hye-Jeong Son, Seho Kweon, Steve Seung-Young Lee, Nayeon Shim, Yoojeong Oh, Hyein Kang, Chaerin Lee, Jihyeon Lee, Jinseong Kim, Hanhee Cho, Kwangmeyung Kim","doi":"10.7150/thno.130510","DOIUrl":"https://doi.org/10.7150/thno.130510","url":null,"abstract":"<p><strong>Rationale: </strong>Proteolysis-targeting chimeras (PROTACs) represent a powerful therapeutic modality for selective protein degradation but often suffer from poor pharmacokinetics and limited tumor-targeting. To overcome these constraints, we developed albumin-binding BRD4-degrading PROTACs (Alb-TACs) with esterase-cleavable maleimide linkers that hitchhike endogenous albumin and enable esterase-responsive BRD4 degradation in tumors.</p><p><strong>Methods: </strong>Alb-TACs were synthesized by conjugating two esterase-cleavable maleimide linkers, bicyclononyne-polyethylene glycol-maleimide (BCN-PEG₂-Mal) or N-(2-aminoethyl)maleimide (AE-Mal), to BRD4-degrading PROTAC (ARV-771), resulting in Alb-TAC#1 and Alb-TAC#2, with distinct albumin- and esterase-binding properties. To select effective Alb-TAC, the binding ability to albumin and esterase-specific cleavage of Alb-TACs were carefully assayed using MALDI-TOF, PAGE, and time-course HPLC. Furthermore, the tumor-targeting efficacy of Alb-TACs was assessed by fluorescence imaging in CT26 tumor-bearing BALB/c mice. Next, we investigated the BRD4 degrading efficiency of Alb-TAC in a cell culture system and in CT26 tumor-bearing mice. Finally, the immunogenic cell death (ICD) and reprogrammed immune cells of Alb-TAC-treated tumors were carefully characterized.</p><p><strong>Results: </strong>Alb-TAC#2 containing the AE-Mal linker exhibited rapid albumin binding, accelerated esterase-responsive activation, and enhanced tumor accumulation compared to ARV-771 and Alb-TAC#1 due to its flexible chemical structure. In the CT26 cell culture system, Alb-TAC#2 efficiently degraded BRD4, resulting in BRD4-deficient cell death. Furthermore, in CT26 tumor-bearing mice, Alb-TAC#2 achieved extensive apoptosis through robust BRD4 degradation, leading to marked downregulation of c-Myc, Bcl-2, and PD-L1. Moreover, Alb-TAC#2 induced hallmarks of ICD (elevated surface CRT, extracellular ATP, and HMGB1) and reprogrammed the tumor microenvironment by enhancing CD8⁺ T cell infiltration, promoting dendritic cell maturation, and reducing regulatory T cell function.</p><p><strong>Conclusions: </strong>This esterase-responsive albumin-binding PROTAC design could overcome pharmacokinetic barriers of conventional BRD4-targeting PROTACs by enhancing tumor-specific delivery and esterase-responsive BRD4 degradation in solid tumors. In summary, esterase-responsive albumin-binding PROTAC is proven as a promising strategy that effectively modulates the pharmacokinetics and therapeutic performance of PROTACs for cancer immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6240-6265"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843164","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":"Current trends regarding types, properties, self-healing mechanisms, and therapeutic strategies for diabetic wounds addressed with polysaccharide-based self-repairing hydrogels: a review.","authors":"Hongkun Xue, Yuxin Bian, Ruoshi Zhang, Ziye Yuan, Haipeng Liu, Chuan Wang, Jiaqi Tan","doi":"10.7150/thno.132479","DOIUrl":"https://doi.org/10.7150/thno.132479","url":null,"abstract":"<p><p>As the global prevalence of diabetes continues to rise, approximately 19% to 34% of diabetes patients will develop chronic wounds or ulcers, which significantly impacts the quality of life of these patients and also imposes a heavy economic burden on the global healthcare system. The traditional treatment methods (debridement, antibiotics, regular dressing changes, hyperbaric oxygen therapy, etc.) are facing numerous challenges, including the increasing problem of bacterial resistance, high treatment costs, and poor long-term efficacy. Therefore, developing efficient and safe new treatment strategies for diabetic wounds has become a current research hotspot. Polysaccharide-based self-healing hydrogels (PSHs) have become one of the most promising wound dressings due to their excellent self-healing ability, good biodegradability, biocompatibility, and multiple biological activities. Unfortunately, there are still limitations in the research on PSHs in the field of diabetes wound treatment. Firstly, this review comprehensively introduces the types of polysaccharides with therapeutic effects on diabetic wounds and their excellent properties. Subsequently, this article systematically reviews the self-healing mechanisms of PSHs and the therapeutic strategies for diabetic wounds. Finally, this paper reviews the challenges and future prospects of PSHs in the clinical transformation of diabetic wounds. The results provide an important reference for the application of PSHs in the field of diabetes wound treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6380-6436"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843220","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":"A peptide-based PROTAC targeting FOXM1 suppresses fibrosis-associated hepatocarcinogenesis.","authors":"Dingyu Wu, Lei Duan, Di Tan, Xinyi Hua, Anping Liang, Ruiping Huai, Shanshan Qi, Zhixian Shang, Shijie Jia, Hui Qi, Xinrong Liu, Jieling Zhao, Yuhong Jiang, Rui Tan, Canquan Mao","doi":"10.7150/thno.129569","DOIUrl":"https://doi.org/10.7150/thno.129569","url":null,"abstract":"<p><strong>Background: </strong>Liver fibrosis is not only a major cause of cirrhosis but also an important risk factor for hepatocellular carcinoma (HCC). Currently, few drugs can effectively reverse established liver fibrosis. FOXM1, a transcription factor aberrantly activated in chronic liver disease, has been implicated in fibrosis-associated hepatocarcinogenesis. Nevertheless, effective pharmacological strategies for targeting FOXM1 are still lacking.</p><p><strong>Methods: </strong>We developed peptide-based proteolysis-targeting chimeras (PROTACs) by conjugating the FOXM1-binding peptide P49 with different E3 ligase ligands. Among them, P49-PROTAC^VHL showed the most potent FOXM1-degrading activity in HCC cells and was selected for further investigation. Its therapeutic efficacy was then evaluated in CCl₄-induced liver fibrosis and DEN/CCl₄-induced hepatocarcinogenesis mouse models. Transcriptome analysis was performed to elucidate the molecular mechanisms by which FOXM1 promotes fibrosis and tumor progression.</p><p><strong>Results: </strong>Mechanistically, P49-PROTAC^VHL recruited FOXM1 to the VHL E3 ligase, leading to its polyubiquitination and subsequent proteasomal degradation. In HCC cells, FOXM1 degradation inhibited proliferation, induced cell cycle arrest, and triggered apoptosis. In the CCl₄ model, P49-PROTAC^VHL attenuated liver fibrosis, as evidenced by reduced collagen deposition, decreased α-SMA expression, and improved liver function. Mechanistic analyses, including dual-luciferase reporter assays, revealed that ADAMTS12 is a candidate transcriptional target of FOXM1. In the DEN/CCl₄ model, P49-PROTAC^VHL modulated the FOXM1-ADAMTS12 axis, thereby mitigating fibrosis and suppressing hepatocarcinogenesis.</p><p><strong>Conclusions: </strong>The FOXM1-ADAMTS12 axis may represent an important molecular link between liver fibrosis and hepatocarcinogenesis. Targeting FOXM1 with peptide-based PROTACs may provide a promising therapeutic strategy to attenuate liver fibrosis and suppress HCC development.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6266-6284"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843238","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":"Glycine promotes cardiomyocyte proliferation and heart regeneration via the GCN2/AKT signaling axis.","authors":"Feng Wang, Xia Zhang, Yang Tang, Yanji He, Wei Wang, Andy Zeng, Lijia Liang, Jing Wang, Chunyu Zeng","doi":"10.7150/thno.127992","DOIUrl":"https://doi.org/10.7150/thno.127992","url":null,"abstract":"<p><strong>Rationale: </strong>While glucose-lipid metabolic remodeling is recognized as a major contributor to cardiomyocytes proliferation, the role of amino acid metabolism in cardiac regeneration remains poorly understood. In this study, glycine was identified as a previously unrecognized pro-proliferative amino acid.</p><p><strong>Methods: </strong>Primary cardiomyocytes, neonatal mice, and adult mouse models of myocardial infarction were employed to investigate the pro-proliferative effects of glycine on cardiomyocytes. Cardiomyocyte proliferation was assessed by immunofluorescence staining of cell-cycle-related markers. Cardiac function was evaluated by echocardiography, and histopathological alterations were examined using Masson's trichrome staining. To overcome the pharmacokinetic limitations of free glycine and enhance therapeutic efficacy, a cardiac-targeted liposomal nanoformulation (LNP@Gly) was developed and applied <i>in vivo</i>. Mechanistic studies were performed using RNA sequencing, Western blotting, co-immunoprecipitation (co-IP), immunostaining, pharmacological inhibition and activation approaches.</p><p><strong>Results: </strong>Exogenous glycine supplementation (700 mg/kg) consistently enhanced cardiomyocyte proliferation across <i>in vitro</i>, neonatal, and adult myocardial infarction models. In infarcted adult hearts, glycine supplementation further improved cardiac function and reduced myocardial fibrosis. A cardiac-targeted liposomal formulation of glycine (LNP@Gly) effectively overcame the pharmacokinetic limitations of free glycine and achieved enhanced therapeutic efficacy at a substantially lower dose (4 mg/kg). At the molecular level, glycine treatment was associated with increased AKT phosphorylation, reduced GCN2 activation, and weakened GCN2-AKT interaction. Pharmacological modulation further supported a critical role for the GCN2-AKT axis in glycine-induced cardiomyocyte proliferation and cardiac repair.</p><p><strong>Conclusions: </strong>These findings identify glycine as a novel metabolic regulator of cardiomyocyte proliferation and cardiac regeneration through modulation of the GCN2-AKT signaling axis. Moreover, the integration of amino acid-specific metabolic regulation with cardiac-targeted nanodelivery represents a translatable therapeutic strategy for ischemic heart disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6220-6239"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843244","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 assessment of extravasation of IL-15-secreting MSLN-CAR-NK-92 cells using tumor transparency imaging.","authors":"Sera Hong, Dohyeon Moon, Seoin Hwang, Mijeong Lee, Duck Cho, Joon Myong Song","doi":"10.7150/thno.125194","DOIUrl":"https://doi.org/10.7150/thno.125194","url":null,"abstract":"<p><strong>Background: </strong>The extravasation of anticancer immune cells is a very important issue that must be understood to improve the anticancer effect of chimeric antigen receptor (CAR)-expressing anticancer immune cell therapy. To date, no study has been reported to quantitatively evaluate the degree of extravasation of anticancer immune cells escaping from tumor blood vessels to the tumor microenvironment (TME) at the microscopic level.</p><p><strong>Methods: </strong>In this study, for the first time, using tumor transparency imaging, the extent of extravasation of CAR-NK and NK cells in pancreatic tumors was determined. we used tumor transparency imaging, which preserves intact vasculature, to accurately measure the extravasation and infiltration of established MSLN-CAR-NK-92 cells and unmodified NK-92 cells in an NSG mouse model of pancreatic cancer. Extravasation was quantified by calculating the volume ratio of cells located inside versus outside tumor vessels.</p><p><strong>Results: </strong>Following intravenous infusion, MSLN-CAR-NK-92 cells showed higher extravasation rates (85.3% vs. 57.4%), penetration depths (185 μm vs. 128 μm), and average extravasated cell counts (7,717 vs. 2,311) compared with NK-92 cells. Further measures of penetration and cytotoxicity also favored MSLN-CAR-NK-92 cells, with CPA50/CPD50 values of 6,887 cells at 88 μm versus 3,509 cells at 45 μm, and CDA50/CDD50 values of 6,350 cells at 102 μm versus 2,023 cells at 48 μm, respectively. These findings highlight the value of extravasation efficiency as a metric for assessing immune cell performance in solid tumors.</p><p><strong>Conclusion: </strong>Considering these results, the extravasation efficiency of anticancer immune cells can be regarded as a valuable indicator for evaluating the effectiveness of CAR constructs designed for NK cells target pancreatic cancer. In this study, we establish a quantitative extravasation imaging platform for evaluating CAR-NK cell trafficking in pancreatic and cholangiocarcinoma tumor models. This approach provides a structured framework for assessing immune cell delivery and therapeutic distribution within the tumor microenvironment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6202-6219"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842747","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":"Mechanomedicine in digestive surgery: a theranostic framework integrating mechanical diagnostics and therapeutic modulation across the perioperative continuum.","authors":"Ning Liu, Xiang Wang, Na Liu, Feng Xu, Ting Wen","doi":"10.7150/thno.133908","DOIUrl":"https://doi.org/10.7150/thno.133908","url":null,"abstract":"<p><p>Digestive surgery remains burdened by anastomotic leakage, postoperative obstruction, and highly variable functional recovery, even when operations are anatomically successful. Accumulating evidence indicates that these complications arise not only from morphology, but also from an unmeasured and unmodulated mechanical microenvironment, including tissue stiffness, anastomotic tension, perfusion-related shear stress, and intra-abdominal pressure. This review outlines a mechanomedicine framework for digestive surgery that treats these mechanical cues as actionable theranostic variables across the perioperative continuum, integrating mechanical diagnostics with targeted mechanical therapeutics. Multiscale biomechanics and mechanotransduction are first considered in relation to healing and fibrosis in the gastrointestinal tract. Preoperative mechanical profiling, using <i>in vivo</i> diagnostic techniques such as magnetic resonance elastography (MRE) and ultrasound shear-wave elastography (SWE), may refine surgical indications and support virtual surgical planning. Intraoperative mechanosensing tools, including functional lumen imaging, quantitative fluorescence perfusion, and portal pressure measurements, may provide real-time diagnostic thresholds to guide anastomotic site selection, reconstruction strategy, and resection extent. <i>In vitro</i> diagnostic platforms, including organ-on-chip models and mechanosensitive biosensors, have further clarified the mechanobiological basis of surgical complications and are informing the design of mechanoresponsive therapeutic systems. Postoperative mechanotherapy, encompassing continuous intra-abdominal pressure monitoring, mechanically tuned scaffolds, early mobilization, and mechanoresponsive drug-delivery systems, may contribute to early warning and personalized rehabilitation. Ethical and equity considerations are also relevant to this framework, including algorithmic bias, data governance, and equitable access across diverse healthcare settings. Together, these advances support a theranostic paradigm in which the same mechanical signals that diagnose risk may also help trigger, guide, or personalize therapy, pointing to a future in which digestive surgery is planned, performed, and followed up with more explicit and integrated control of the mechanical microenvironment to reduce complications and improve long-term function.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6285-6314"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842428","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":"Unraveling autophagy-metabolism crosstalk in cancer: Molecular insights and therapeutic strategies.","authors":"Haoyou Wang, Qianqian Yang, Yingying Lu, Cheng Du, Wei Wang, Lan Zhang","doi":"10.7150/thno.132362","DOIUrl":"https://doi.org/10.7150/thno.132362","url":null,"abstract":"<p><p>Autophagy is a catabolic process essential for the degradation and recycling of damaged proteins and organelles, thereby contributing to the maintenance of cellular homeostasis and the integrity of the intracellular environment. Although autophagy serves protective physiological functions, its involvement in various diseases, particularly cancer, is complex and context-dependent. In the context of tumor development, autophagy plays two distinct roles. During the early stages of tumorigenesis, it functions as a tumor suppressor by preserving genomic stability. In later stages, however, it promotes tumor growth, supports the survival of cancer cells, and contributes to therapeutic resistance. Cancer cells are known to change their metabolic processes to support growth and division. Autophagy and metabolism work together, enabling cells to utilize both external and internal resources to generate energy and synthesize new molecules. This interaction is especially important in the stressful environment of tumors, like when there's not enough food or oxygen. In these situations, autophagy helps the tumor adapt metabolically and grow by breaking down and reusing parts inside the cell. In this review, we systematically examine the role of autophagy as a key regulator that coordinates diverse metabolic programs in cancer cells. We focus on central metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, as well as emerging regulatory networks involving nucleotide metabolism and mitochondrial metabolism. Importantly, we highlight how these metabolic pathways are dynamically integrated through autophagy to facilitate tumor adaptation, support metabolic plasticity, and drive therapeutic resistance.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6315-6349"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843070","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":"A tumor-targeted heptamethine cyanine dye suppresses triple-negative breast cancer by induction of lethal autophagy.","authors":"Sang-Hyo Kim, Yoonbin Park, Hwa-Yeong Jin, Taewon Lee, Sungsu Lee, Moon Suk Kim, Hoon Hyun","doi":"10.7150/thno.130353","DOIUrl":"https://doi.org/10.7150/thno.130353","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is a highly invasive type of breast cancers that is characterized by the absence of hormone receptors and HER2 protein, thereby relying mostly on surgical intervention and cytotoxic chemotherapy. Recently, autophagy in TNBC progression has emerged as an important role for more effective TNBC treatments.</p><p><strong>Methods: </strong>Since autophagy is a critical determinant of cell fate, depending on the context and stress level, we newly develop a hydrophilic anionic heptamethine cyanine dye (named TNBC800) for the treatment of TNBC by induction of lethal autophagy.</p><p><strong>Results: </strong>TNBC800 induces autophagy-mediated immunogenic cell death to exert targeted therapeutic effects on MDA-MB-231 xenografts. In terms of molecular mechanism, the TNBC800 can be imported into MDA-MB-231 cells through the endosomal sorting complex required for transport (ESCRT) pathway. Consequently, TNBC800 elevates the intracellular level of reactive oxygen species (ROS) and induces autophagic stress, demonstrated by increased LC3B accumulation, which contributes to cell apoptosis and suppression of tumor proliferation. Finally, we confirm a substantial increase in the presence of M1 macrophages in spleen and NK cells in tumors over the course of treatment.</p><p><strong>Conclusion: </strong>This study introduces a potentially effective strategy for enhancing TNBC treatment efficacy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6366-6379"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843149","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":"CIAPIN1 functions as a redox-sensitive transcriptional repressor of <i>Tp53</i> during vascular remodeling.","authors":"Seongpyo Lee, Joo-Hui Han","doi":"10.7150/thno.124965","DOIUrl":"https://doi.org/10.7150/thno.124965","url":null,"abstract":"<p><strong>Background: </strong>Phenotypic switching in vascular smooth muscle cells (VSMCs) is a major driver of pathological vascular remodeling, including atherosclerosis and restenosis. Although p53 is a key regulator of VSMC homeostasis, the precise molecular mechanisms responsible for suppressing p53 expression during growth factor-induced phenotypic transitions remain incompletely understood. The present study identifies cytokine-induced apoptosis inhibitor 1 (CIAPIN1) as a novel redox-sensitive regulator of the p53 signaling axis.</p><p><strong>Methods: </strong>Primary cultured VSMCs and a rat carotid balloon injury model were used to investigate the role of CIAPIN1 in VSMC dynamics. CIAPIN1 expression was modulated using both gain- and loss-of-function approaches. The interaction between CIAPIN1 and the <i>Tp53</i> promoter was examined by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Redox-dependent subcellular trafficking of CIAPIN1 was assessed using N-acetylcysteine (NAC), Ivermectin (IVM) and site-directed mutagenesis of the nuclear localization signal (NLS).</p><p><strong>Results: </strong>In human atherosclerotic lesions, CIAPIN1 expression was markedly upregulated, whereas <i>Tp53</i> mRNA levels were significantly lower compared with healthy controls. Stimulation with PDGF-BB increased CIAPIN1 expression and the induced CIAPIN1 protein directly bound to specific consensus sites in the <i>Tp53</i> promoter, thereby repressing its transcription. This CIAPIN1-mediated suppression of p53 promoted a switch toward the synthetic phenotype in VSMCs, accelerating proliferation and migration. These effects were substantially attenuated by CIAPIN1 knockdown or by restoring p53 expression. Mechanistically, PDGF-BB triggered reactive oxygen species (ROS) production, which promoted the nuclear translocation of CIAPIN1 through a functional C-terminal NLS (residues 236-239) via the classical importin-α/β pathway. Blocking this trafficking axis with the ROS scavenger NAC, the importin inhibitor IVM or genetic deletion of the NLS (∆236-239) restored p53 expression and significantly reduced neointimal formation <i>in vivo</i>.</p><p><strong>Conclusions: </strong>CIAPIN1 functions as a redox-sensitive transcriptional repressor of <i>Tp53</i>, driving VSMC phenotypic switching and neointimal hyperplasia. These findings highlight CIAPIN1 as a promising and specific therapeutic target for the treatment of proliferative vascular disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6350-6365"},"PeriodicalIF":13.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843241","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":"Elevated target expression by dual PD-L1 and 4-1BB engagement is associated with ⁸⁹Zr-PD-L1x4-1BB bispecific Mabcalin tumor uptake.","authors":"Claudia A J van Winkel, Xiaoyu Fan, Danique Giesen, Glenn Gauderat, Steven de Jong, Thomas Jaquin, Wim Timens, Agathe Lepissier, Marleen Richter, Stefan Grüner, Nicole Andersen, Laurent Laboureur, Lucia Pattarini, Helene Lelièvre, Elisabeth G E de Vries, Aizea Morales-Kastresana, Marjolijn N Lub-de Hooge","doi":"10.7150/thno.123930","DOIUrl":"https://doi.org/10.7150/thno.123930","url":null,"abstract":"<p><p>The antibody-anticalin fusion protein (Mabcalin) targeting programmed cell death-ligand 1 (PD-L1) and T-cell costimulatory immunoreceptor CD137 (4-1BB) is designed to enhance T-cell reactivity while preventing T-cell inhibition by PD-L1/programmed cell death protein 1 (PD-1) checkpoint blockade. Using positron emission tomography (PET) imaging and <i>ex vivo</i> analysis, we investigated the factors influencing biodistribution, tumor uptake, and the influence of dose and target presence. <b>Methods</b> Murine or human PD-L1-reactive and human 4-1BB reactive Mabcalins (mPD-L1xh4-1BB and hPD-L1xh4-1BB) were generated, radiolabeled with ⁸⁹Zr, and administered to human 4-1BB knock-in (h4-1BB KI) or wild-type (WT) mice bearing PD-L1-positive mouse MC38 tumors. Mice underwent serial PET imaging on days 1, 2, and 4 or on days 2, 4, and 7 post intravenous injection, followed by <i>ex vivo</i> biodistribution. The intratumoral distribution of 2 protein doses of ⁸⁹Zr-radiolabeled mPD-L1xh4-1BB and hPD-L1xh4-1BB was examined using autoradiography on tumor tissue sections. These tumor sections were immunohistochemically stained for PD-L1, CD3, CD8, and 4-1BB to link uptake to target expression levels. <b>Results</b> ⁸⁹Zr-mPD-L1xh4-1BB, able to bind mPD-L1 and h4-1BB in h4-1BB KI mice, predominantly showed specific and rapid dose-dependent lymphoid tissue uptake. The tumor uptake of 200 µg ⁸⁹Zr-mPD-L1xh4-1BB in h4-1BB KI mice was also specific and increased over time. Tumor uptake in this group, where both targets PD-L1 and 4-1BB could be bound, was > 4-fold higher than in the groups that could bind only PD-L1 or 4-1BB. Dual PD-L1 and 4-1BB Mabcalin engagement at a therapeutic dose also resulted in elevated tumor protein expression levels for PD-L1, CD3, and CD8, which were lower when only PD-L1 or 4-1BB was engaged. The lowest expression was observed with the Mabcalin binding non-specifically (<i>P</i> _trend≤0.01 for PD-L1 and CD3, <i>P</i> _trend≤0.05 for CD8). <b>Conclusion</b> The biodistribution of mPD-L1xh4-1BB is specific, dose-dependent, and associated with the elevated target expression resulting from dual PD-L1 and 4-1BB engagement.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6184-6201"},"PeriodicalIF":13.3,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843177","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}