TheranosticsPub Date : 2025-08-16eCollection Date: 2025-01-01DOI: 10.7150/thno.115080
Yue Yin, Shijie Zhao, Wei Li, Yuan Cui, Thanh Loc Nguyen, Ge Gao
{"title":"<i>In situ</i> reprogramming of fibroblasts into antigen-presenting pseudo-dendritic cells via IFN-β-engineered protoplast-derived exosomes delivered by microneedle arrays to enhance adaptive immunity.","authors":"Yue Yin, Shijie Zhao, Wei Li, Yuan Cui, Thanh Loc Nguyen, Ge Gao","doi":"10.7150/thno.115080","DOIUrl":"10.7150/thno.115080","url":null,"abstract":"<p><p><b>Rationale</b>: Dendritic cells (DCs) play a crucial role in adaptive immune responses; however, <i>ex vivo</i> differentiation strategies face operational complexities and reduced cellular viability. <i>In situ</i> reprogramming of resident cells into antigen-presenting cells represents a promising alternative approach for enhancing local immune responses. <b>Methods</b>: We initially introduce the novel concept of pseudo-DCs, <i>in situ</i> transforming intradermal fibroblasts into DC-like cells using an engineered exosome-loaded microneedle (MN) array. Specifically, engineered nano-protoplasts expressing interferon-beta (IFN-β) and loaded with varicella-zoster virus glycoprotein E (VZV gE) were used to stimulate DCs and derive immunostimulatory exosomes. These exosomes were integrated into a microarray-based delivery system for intradermal application. <b>Results</b>: The engineered exosomes (IdE@E) induced resident fibroblasts to upregulate DC surface co-stimulatory markers (CD80/86) and effectively present the model antigen. Transcriptome analysis also revealed significant upregulation of genes associated with immune response and antigen presentation in IdE@E-treated cells. <i>In vivo</i> studies demonstrated that MN array-delivered IdE@E effectively induced the expression of DC and activation markers from fibroblasts in dermis. Furthermore, MN array-delivered IdE@E significantly elevated the population of IFN-γ<sup>+</sup>CD8<sup>+</sup> T cells in both lymph nodes and spleen, indicating enhanced local and systemic immune responses. <b>Conclusions</b>: This novel <i>in situ</i> reprogramming method represents a paradigm shift in precision immunotherapies, leveraging exosome-mediated cellular mimicry to enhance adaptive immunity without complete cellular transformation. This scalable framework holds significant promise for immunotherapy and could revolutionize personalized immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9179-9199"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081591","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}
TheranosticsPub Date : 2025-08-16eCollection Date: 2025-01-01DOI: 10.7150/thno.118409
Bo Hyun Yoon, Jinho Kim, Sandip Sengupta, Chan-Jung Park, Minjoo Ko, Ji Hee Kang, Young Tag Ko, Yeji Kim, Seung Min Lim, Yoonhee Bae, MooYoung Choi, Yunyeong Jang, Ho Jeong Kwon, Hyo Jin Son, Hee Jin Kim, Taebo Sim, Keun-A Chang, Myung-Shik Lee
{"title":"Targeted autophagic clearance of Tau protects against Alzheimer's disease through amelioration of Tau-mediated lysosomal stress.","authors":"Bo Hyun Yoon, Jinho Kim, Sandip Sengupta, Chan-Jung Park, Minjoo Ko, Ji Hee Kang, Young Tag Ko, Yeji Kim, Seung Min Lim, Yoonhee Bae, MooYoung Choi, Yunyeong Jang, Ho Jeong Kwon, Hyo Jin Son, Hee Jin Kim, Taebo Sim, Keun-A Chang, Myung-Shik Lee","doi":"10.7150/thno.118409","DOIUrl":"10.7150/thno.118409","url":null,"abstract":"<p><p><b>Background:</b> Lysosomal dysfunction could be an underlying cause of Alzheimer's disease, with Tau oligomer being an important inducer or amplifier of lysosomal stress associated with the disease. Tau oligomer is a well-known substrate of autophagy, and selective degradation of Tau with Tau-specific autophagy degrader might be feasible. <b>Methods:</b> Tau-specific autophagic degraders were synthesized by combining leucomethylene blue, linkers and a lysosomal degradation tag (Autac). Tau clearance and changes of Tau-mediated lysosomal stress by these degraders were studied <i>in vitro</i>. <i>In vivo</i> effects of a Tau-specific degrader were investigated employing a combined Tau/Aβ mutant mouse model characterized by an accelerated onset of neurological deficits. Human relevance was investigated using induced pluripotent stem cell (iPSC)-derived neuronal cells from an Alzheimer's disease patient. <b>Results</b>: Among Tau-specific Autac degraders, TauAutac-3 (TA-3) efficiently degraded Tau oligomer and monomer, an effect inhibited by bafilomycin A1, suggesting lysosomal Tau degradation. TA-3 treatment induced LC3, K63, OPTN or NDP52 puncta, which was partially colocalized with Tau oligomer. Signs of lysosomal stress, such as galectin-3 puncta, pHluorin fluorescence, altered lysosomal pH and CHMP2B recruitment, induced by Tau expression were reversed by TA-3. Autophagy impairment by Tau expression <i>in vitro</i>, likely due to lysosomal stress, was also reversed by TA-3. <i>In vivo</i>, TA-3 administration markedly reduced the accumulation of both Tau and Aβ in 6xTg mice, which was associated with amelioration of Tau-mediated lysosomal stress and autophagy impairment. Neuroinflammation characterized by increased numbers of GFAP<sup>+</sup> glial cells and Iba1<sup>+</sup> microglial cells, was also reduced following TA-3 administration. TA-3 remarkably improved neurologic deficits in 6xTg mice, such as impaired memory and reduced exploratory behavior. TA-3 reduced Tau and phospho-Tau accumulation in iPSC-derived neuronal cells from an Alzheimer's disease patient. <b>Conclusion:</b> These results suggest that Tau-specific autophagic (Autac) degraders could serve as novel therapeutic agents for Alzheimer's disease through reduction of Tau-mediated lysosomal stress.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9240-9260"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081739","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":"Triple-targeting nanosystems with synergistic effects on iron Trojan horse, fluoroquinolone antibiotics, and photodynamic therapy specifically kill intracellular MRSA.","authors":"Kuiyu Meng, Liwen Yuan, Lulu Feng, Yaoyao Zhang, Hao Wu, Jie Zhang, Mubbashar Abbas, Wei Qu, Dongmei Chen, Shuyu Xie","doi":"10.7150/thno.109374","DOIUrl":"10.7150/thno.109374","url":null,"abstract":"<p><p><b>Rationale:</b> Iron is necessary for the survival of microorganisms. The uptake network is highly expressed by host cells and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and competes with heme iron. Gallium porphyrin (GaPR), a heme mimetic compound, was synthesized to develop an innovative nanosystem as a triple-targeting agent for uptake network recognition. GaPR is also used as a dual therapeutic molecule of \"iron trojan horse\" and photosensitizer to achieve synergistic antibacterial effects with levofloxacin to eradicate intracellular MRSA-a problem that conventional therapeutic techniques cannot overcome due to limited drug penetration, antibiotic resistance, and off-target effects. <b>Methods:</b> A library of hemimetic compounds was synthesized. GaPR was selected as the optimal candidate owing to its antibacterial activities and competitive binding affinity for iron uptake receptors. The optimal GaPR and the photosensitizer tetrakis-(4-carboxyphenyl)-porphyrin (TCPP) were used to prepare a levofloxacin (Lev)-loaded zirconium-based organometallic scaffold (Lev-GaPR-PCN). Hyaluronic acid (HA) was linked to the Lev-GaPR-PCN surface via ROS-reactive thioketal bonds (TK). The triple-targeting performance and synergistic efficacy of HA-Lev-GaPR-PCN against intracellular MRSA were tested <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> GaPR showed strong bactericidal activity against MRSA by interfering with iron metabolism. GaPR-PCN exhibited excellent binding ability with host-derived heme-binding proteins (Hpx/LRP1 and Hpg/CD163) and the iron-regulated surface determinant (Isd) system of MRSA for infection site, infected cell, and intracellular targeting. HA coating enabled covert circulation and decreased nonspecific uptake by healthy cells (< 5% fluorescence intensity after 6 h) while promoting infection-induced release via hyaluronidase and ROS. <i>In vitro</i>, HA-Lev-GaPR-PCN achieved 3.42-fold greater colocalization with intracellular MRSA (Pearson correlation: 0.41 vs. 0.12 for PCN-224 controls) and decreased the extracellular/intracellular minimum inhibitory concentrations (MICs) of Lev under PDT from 8/64 μg/mL to 1/2 μg/mL. <i>In vivo</i>, it resulted in prolonged retention (72 h vs. 36 h) and a 1.5-2.5-fold greater fluorescence intensity at infection sites for non-HA nanosystems. Compared to Lev alone, it decreased the bacterial load by 501-fold (2.7 log) and abscesses (diameter: 0.6 cm vs. 3.3 cm) by combining chemical, metabolic, and physical antibacterial mechanisms without causing toxic effects. <b>Conclusion:</b> This study represents a paradigm shift in intracellular infection therapy for MRSA and other resistant bacteria using a hemimetic compound as a triple-targeting and dual therapeutic agent that provides a streamlined, clinically feasible solution with high efficacy and specificity.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9326-9343"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081671","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":"Dimeric CCK2R radiotheranostic tracers synergize with mTOR inhibition for enhanced tumor therapy.","authors":"Linjie Bian, Zheyi Wang, Panli Li, Simin He, Jianping Zhang, Xiaoping Xu, Xiangwei Wang, Shaoli Song","doi":"10.7150/thno.117021","DOIUrl":"10.7150/thno.117021","url":null,"abstract":"<p><p><b>Purpose:</b> The cholecystokinin-2 receptor (CCK2R) is highly expressed in several neuroendocrine cancers, particularly in medullary thyroid carcinoma (MTC) and small cell lung cancer (SCLC) and represents a promising target for radiotheranostic applications. Several minigastrin-derived analogs, such as DOTA-MGS5 and DOTA-CCK-66, have demonstrated favorable tumor targeting and imaging performance. Building on these advances, we developed and evaluated a novel dimeric CCK<sub>2</sub>R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. <b>Experimental Design:</b> We designed a dimeric CCK<sub>2</sub>R-targeted agent, DOTA-CCK<sub>2</sub>R-dimer, labeled with <sup>68</sup>Ga for PET imaging and <sup>177</sup>Lu for radionuclide therapy. Furthermore, we combined [<sup>177</sup>Lu]Lu-DOTA-CCK<sub>2</sub>R-dimer with the mTOR inhibitor RAD001 and used single-cell RNA sequencing (scRNA-seq) to investigate the mechanisms of radiosensitization. <b>Results:</b> Compared with its monomeric counterpart [<sup>68</sup>Ga]Ga-DOTA-CCK-66, [<sup>68</sup>Ga]Ga-DOTA-CCK<sub>2</sub>R-dimer demonstrated superior tumor targeting <i>in vivo</i>. Tumor uptake reached 26.13 ± 6.21 %ID/g at 2 h post-injection, which was significantly greater than that of the monomeric tracer (19.63 ± 3.35 %ID/g, <i>p</i> < 0.05). Additionally, [<sup>177</sup>Lu]Lu-DOTA-CCK<sub>2</sub>R-dimer selectively eliminated highly proliferative and poorly differentiated tumor cell subpopulations. Combination treatment with RAD001 improved therapeutic efficacy by suppressing glutathione-mediated detoxification and increasing oxidative stress. Furthermore, glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator that modulates radiosensitivity. Conclusions: DOTA-CCK<sub>2</sub>R-dimer exhibits favorable <i>in vivo</i> stability, notable tumor retention, and excellent imaging performance. Combining this agent with mTOR inhibition offers a synergistic strategy to sensitize tumors to radiotherapy, providing a promising approach for treating refractory CCK<sub>2</sub>R-positive malignancies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9306-9325"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081588","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}
TheranosticsPub Date : 2025-08-16eCollection Date: 2025-01-01DOI: 10.7150/thno.117725
Tianyi Wu, Yun Teng, Dawei Song, Yuqi Yang, Huaishuang Shen, Xiao Sun, Rui Chen, Leyu Zhao, Xianggu Zhong, Qi Yan, Junjie Niu, Jun Ge, Liang Cheng, Jun Zou
{"title":"A strategy targeting ferroptosis for mitochondrial reprogramming and intervertebral disc degeneration therapy.","authors":"Tianyi Wu, Yun Teng, Dawei Song, Yuqi Yang, Huaishuang Shen, Xiao Sun, Rui Chen, Leyu Zhao, Xianggu Zhong, Qi Yan, Junjie Niu, Jun Ge, Liang Cheng, Jun Zou","doi":"10.7150/thno.117725","DOIUrl":"10.7150/thno.117725","url":null,"abstract":"<p><p><b>Background:</b> Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet current therapies fail to reverse the degenerative process or restore disc function. Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has been implicated in IVDD progression. <b>Methods:</b> We synthesized Deferoxamine mesylate (DFOM)-loaded cerium oxide nanoparticles (DFOM@CeO<sub>2</sub>) as a novel ferroptosis-targeting therapeutic. <b>Results:</b> DFOM@CeO<sub>2</sub> exhibited dual functionality by scavenging reactive oxygen species (ROS) and chelating excess iron, thereby protecting nucleus pulposus (NP) cells from ferroptosis and extracellular matrix (ECM) degradation. DFOM@CeO<sub>2</sub> demonstrated strong antioxidant capacity, effectively reducing iron accumulation and lipid peroxidation, and restoring glutathione peroxidase 4 (GPX4) expression in NP cells. Furthermore, DFOM@CeO<sub>2</sub> improved mitochondrial respiratory chain function, reduce mitochondrial ROS production and prevent mitochondrial dysfunction. In a rat model of IVDD, DFOM@CeO<sub>2</sub> significantly preserved disc height, reduced ECM degradation, and demonstrated superior therapeutic efficacy compared with DFOM or CeO<sub>2</sub> alone. Transcriptome analysis revealed that DFOM@CeO<sub>2</sub> modulates key ferroptosis-related genes and promotes mitochondrial reprogramming. <b>Conclusions:</b> These findings highlight DFOM@CeO<sub>2</sub> as a promising therapeutic strategy for IVDD, targeting both ferroptosis and mitochondrial dysfunction.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9159-9178"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081597","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}
TheranosticsPub Date : 2025-08-16eCollection Date: 2025-01-01DOI: 10.7150/thno.119545
Sun-Hee Cho, Byeongkwon Choi, Jisun Lee, Yu-Sun Lee, Mi-Ock Baek, You-Jeung Lee, Chae-Ok Gil, Min-Kyung Choi, Sana Abdul Khaliq, Syeda Maham, Jae-Kyung Hyun, Gahyun Roh, Huijeong Choi, Sowon Lee, Seo-Hyeon Bae, Seonghyun Lee, Hyo-Jung Park, Jae-Hun Ahn, Na-Young Lee, Byeong-Cheol Kang, Young Kyo Seo, Byung-Kwan Lim, Jae-Hwan Nam, Mina Rho, Mee-Sup Yoon
{"title":"ApoE deficiency protects from mRNA vaccine-induced mitochondrial dysfunction at the injection site under metabolic stress.","authors":"Sun-Hee Cho, Byeongkwon Choi, Jisun Lee, Yu-Sun Lee, Mi-Ock Baek, You-Jeung Lee, Chae-Ok Gil, Min-Kyung Choi, Sana Abdul Khaliq, Syeda Maham, Jae-Kyung Hyun, Gahyun Roh, Huijeong Choi, Sowon Lee, Seo-Hyeon Bae, Seonghyun Lee, Hyo-Jung Park, Jae-Hun Ahn, Na-Young Lee, Byeong-Cheol Kang, Young Kyo Seo, Byung-Kwan Lim, Jae-Hwan Nam, Mina Rho, Mee-Sup Yoon","doi":"10.7150/thno.119545","DOIUrl":"10.7150/thno.119545","url":null,"abstract":"<p><p><b>Rationale:</b> The local tissue effects of mRNA vaccination remain incompletely understood. We investigated how SARS-CoV-2 mRNA vaccination impacts injection site tissues in the context of different metabolic states and apolipoprotein E (ApoE) status. <b>Methods:</b> We administered intramuscular SARS-CoV-2 mRNA vaccination to wild-type and ApoE-deficient mice under regular and high-fat diets, as well as macaques. We performed transcriptomic analysis, ultrastructural examination, functional assessments including grip strength testing, and immunological evaluations to characterize local and systemic responses. <b>Results:</b> Intramuscular vaccination induced localized injury characterized by inflammation, mitochondrial disruption, and reduced grip strength in wild-type animals. Transcriptomic and ultrastructural analyses revealed denervation-associated changes, downregulation of mitochondrial genes, cristae disruption, and activation of immune and apoptotic pathways. ApoE-deficient mice, particularly under Western diet conditions, demonstrated protection from mitochondrial and inflammatory responses despite comparable vaccine expression levels. This protection involved attenuated mitochondrial gene downregulation, preserved mitochondrial DNA integrity, and reduced inflammatory responses. While ApoE deficiency resulted in diminished antibody production, T cell responses remained intact, indicating selective immunomodulation. Cardiac tissue showed minimal transcriptional changes, confirming injection site-specific effects. <b>Conclusions:</b> ApoE deficiency provides protection against vaccine-induced mitochondrial and inflammatory damage at the injection site, with enhanced protective effects under metabolic stress conditions. These findings reveal important interactions between metabolic status, lipid metabolism, and local vaccine responses that may inform vaccination strategies in different patient populations.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"8964-8984"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081571","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}
TheranosticsPub Date : 2025-08-16eCollection Date: 2025-01-01DOI: 10.7150/thno.114797
Jiaxuan Yang, Jiahui Sun, Zili Liu, Xia Tang, Yunyun Hu, Weida Shen, Yicheng Xie, Yue Jin, Haifeng Li, Xuekun Li, Yanjun Jiang, Matthew Tak Vai Chan, William Ka Kei Wu, Zhigang Liu, Xiaodong Liu, Yaoqin Hu, Jinpiao Zhu, Daqing Ma
{"title":"Dopamine D2 receptor modulating mPFC-BLA circuit contributes to chronic sleep deprivation-induced memory impairment in mice.","authors":"Jiaxuan Yang, Jiahui Sun, Zili Liu, Xia Tang, Yunyun Hu, Weida Shen, Yicheng Xie, Yue Jin, Haifeng Li, Xuekun Li, Yanjun Jiang, Matthew Tak Vai Chan, William Ka Kei Wu, Zhigang Liu, Xiaodong Liu, Yaoqin Hu, Jinpiao Zhu, Daqing Ma","doi":"10.7150/thno.114797","DOIUrl":"10.7150/thno.114797","url":null,"abstract":"<p><p><b>Background:</b> Chronic sleep deprivation (CSD) affects the orchestration of neural networks, leading to cognitive impairment, but the underlying molecular and neural circuitry mechanisms remain unknown. <b>Methods:</b> Mice underwent a two-week CSD regimen, followed by spatial memory assessment using the Y-maze test and EEG gamma oscillation analysis. Dopamine D2 receptor (Drd2) expression in the medial prefrontal cortex (mPFC) was evaluated using transcriptomic and immunofluorescent analysis. The role of Drd2 in CSD-induced memory deficits was examined through local infusion of Drd2 agonists or antagonists into the mPFC. Neural circuit tracing, fiber photometry, and opto-chemogenetic approaches were used to assess Drd2 in the gating of the mPFC-basolateral amygdala (BLA) circuit-mediated memory impairment induced by CSD. <b>Results:</b> CSD disinhibited dopaminergic input to the mPFC and impaired spatial memory in mice. A significant increase in Drd2 expression was found in the layers II/III of the mPFC after CSD. Infusion of Drd2 agonist into the mPFC induced memory deficits in naïve mice, while administration of the Drd2 antagonist reversed memory impairment caused by CSD. Drd2 was found to co-localize with Ca<sup>2+</sup>/calmodulin-dependent protein kinase IIα (CaMKIIα<sup>+</sup>) neurons in the mPFC that project to the basolateral amygdala (BLA). Activation of CaMKIIα<sup>+</sup> neurons restored memory impairment induced by CSD through enhancing mPFC-to-BLA output and reversed memory defects induced by the Drd2 agonist. <b>Conclusion:</b> Our findings demonstrated that excessive Drd2 signaling leads to cognitive impairment following CSD by suppressing mPFC-BLA neurotransmission, suggesting a possible therapeutic value of dopamine D2 receptor antagonists in relieving CSD-induced cognitive decline.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9073-9090"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081618","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":"Tumor-responsive cuproptosis nanoinducer realizing efficient PANoptosis for enhanced cancer immunotherapy.","authors":"Kaiqing Yun, Xiaohong Yu, Shuang Liang, Qingling Wang, Ziyi Zhang, Yue Han, Yueyang Zhao, Yuxuan Peng, Lang Rao, Yong Cui, Zhaohui Wang","doi":"10.7150/thno.115275","DOIUrl":"10.7150/thno.115275","url":null,"abstract":"<p><p><b>Rationale:</b> The induction of multiple forms of regulated cell death (RCD) presents a promising approach for antitumor immunotherapy. However, the heterogeneous tumor microenvironment (TME) limits the efficacy of single-mode RCD induction strategies. <b>Methods:</b> We engineered Elesclomol-Cu@PDPA nanoparticles (PEC NPs) designed to induce cuproptosis and subsequent PANoptosis. These NPs remain stable during circulation but rapidly dissociate in the acidic TME, releasing Cu<sup>2+</sup> and Elesclomol to trigger cuproptosis. <b>Results:</b> The cuproptosis induced by PEC NPs resulted in PANoptosis of tumor cells. This process stimulated immunogenic cell death and activated a systemic immune response by promoting immune cell infiltration and reprogramming the immunosuppressive TME. PEC NPs demonstrated potent tumor growth inhibition and exhibited a synergistic antitumor effect when combined with immune checkpoint blockade therapy. <b>Conclusions:</b> This study provides a robust strategy utilizing PEC NPs to induce efficient cuproptosis and PANoptosis for enhanced immunotherapy. It offers new insights into boosting tumor immunogenicity through the activation of multiple RCDs pathways.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9294-9305"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081744","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 first abdominal aortic aneurysm organoid model replicates complex microenvironment for <i>in vitro</i> disease study.","authors":"Jiaxuan Feng, Mingjie Rong, Yudong Sun, Guanglang Zhu, Guangkuo Wang, Jiping Liu, Chen Wang, Jian Zhang, Xiaochen Ma, Junyi Yan, Yaojie Wang, Youjin Li, Yu Ning, Chunhui Cai, Xinxin Han","doi":"10.7150/thno.118193","DOIUrl":"10.7150/thno.118193","url":null,"abstract":"<p><p><b>Background:</b> Abdominal Aortic Aneurysm (AAA) is a critical global health issue, affecting an estimated up to 8% of men over 65, with a complex etiology involving smoking, age and gender. However, the lack of specific drug treatments underscores the need for a robust in vitro model to advance our comprehension of AAA pathophysiology and serve as an ex vivo surrogate for drug testing. <b>Methods:</b> This study introduces an innovative AAA patient-derived organoid (PDO) model using a non-enzymatic procedure, a Matrigel-free system, and specialized organoid culture medium, leveraging 3-dimensional (3D) cultures to replicate the disease's microenvironment. The stability of this culture system was assessed through microscopic observation, H&E staining, immunohistochemistry (IHC), viability assays, and whole-genome sequencing (WES). Additionally, we conducted pharmacological assessments to explore the effects of drug treatments on AAA PDO. <b>Results:</b> Our model maintains aortic morphological integrity and pathological phenotypes, incorporates the immune microenvironment (validated by IHC markers for macrophages and lymphocytes), and adjacent tissues (loose connective tissue and vegetative blood vessels). The model demonstrates remarkable stability, confirmed by consistent genetic mutation sites throughout cultivation via WES, and cell survival after five weeks in vitro via live-cell staining. Preliminary pharmacological assessments show promising efficacy, with distinct responses to 1 μM metformin, 1 μM RU.521, or 1 μM STING-IN-2 treatments for 48 h via mass spectrometry. <b>Conclusions:</b> The AAA organoid model, to the best of our knowledge, is the first reported abdominal aortic aneurysm PDO model, and signifies a promising step towards therapeutic treatment options for AAA, potentially complementing existing surgical approaches.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9029-9046"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081694","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":"Macrophage-derived KIF13B interacts with USP9X to attenuate abdominal aortic aneurysm development by potentiating TFEB stability.","authors":"Jingxuan Chen, Yitong Xu, Huahui Yu, Yiran Liu, Guolin Miao, Yufei Han, Liwen Zheng, Zeyu Cai, Zihao Zhou, Jinxuan Chen, Sijing Shi, Pingping Lai, Wenxi Zhang, Lianxin Zhang, Si Mei, Yinqi Zhao, Ling Zhang, Wei Huang, Yuhui Wang, Dongyu Zhao, Wei Kong, Yanwen Qin, Erdan Dong, Xunde Xian","doi":"10.7150/thno.118958","DOIUrl":"10.7150/thno.118958","url":null,"abstract":"<p><p><b>Rationale:</b> Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disorder for which there is no effective medication to date. Kinesin family member 13b (KIF13B), a vital motor protein, has been recently identified as a novel regulator of lipid metabolism. However, the role of KIF13B in AAA development has not been documented. <b>Methods:</b> We determined the expression of KIF13B in aortic tissues from clinical patients and porcine pancreatic elastase (PPE) or angiotensin II (ANG II)-induced AAA mouse models. To investigate the influence of KIF13B on AAA expansion, we established global, myeloid cell-specific and vascular smooth muscle cell (VSMC)-specific conditional <i>Kif13b</i>-deficient mice in PPE and/or ANG II-induced AAA models. <b>Results:</b> RNA-seq data from GEO database (GSE57691) revealed a significant decrease in <i>KIF13B</i> gene expression within the aortic tissues of patients with AAA. KIF13B protein levels were largely reduced in aortic tissue samples from patients and two mouse models with AAA. Complete inactivation of <i>Kif13b</i> or depleting <i>Kif13b</i> from myeloid cells but not smooth muscle cells (SMCs) exacerbated AAA development. Mechanistic studies identified transcription factor EB (TFEB) as a critical downstream target of KIF13B. KIF13B stabilized and upregulated TFEB by enhancing its deubiquitination through an interaction with deubiquitinase USP9X to maintain the proper function of lysosomes, thus inhibiting the senescence-associated secretory phenotype (SASP) and proinflammatory response of macrophages. Moreover, restoration of macrophage <i>Kif13b</i> or senolytic therapy dramatically mitigated AAA expansion <i>in vivo</i>. <b>Conclusions:</b> In the present study, we provided a new insight into the pathogenesis of AAA and defined a KIF13B-USP9X-TFEB axis that is essential for the regulation of macrophage function, suggesting that macrophage-derived <i>Kif13b</i> is a beneficial regulator of vascular homeostasis and targeting KIF13B could be a potential therapeutic approach for the treatment of human AAA disease in future clinical trial.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9114-9130"},"PeriodicalIF":13.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081598","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}