Theranostics最新文献

{"title":"Erratum: An electroporation strategy to synthesize the membrane-coated nanoparticles for enhanced anti-inflammation therapy in bone infection: Erratum.","authors":"Miusi Shi, Kailun Shen, Bin Yang, Peng Zhang, Kangle Lv, Haoning Qi, Yunxiao Wang, Mei Li, Quan Yuan, Yufeng Zhang","doi":"10.7150/thno.121003","DOIUrl":"https://doi.org/10.7150/thno.121003","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.7150/thno.48407.].</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9200"},"PeriodicalIF":13.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081603","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}

{"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⁺CD8⁺ 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}

{"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⁺ glial cells and Iba1⁺ 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 CCK₂R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. <b>Experimental Design:</b> We designed a dimeric CCK₂R-targeted agent, DOTA-CCK₂R-dimer, labeled with ⁶⁸Ga for PET imaging and ¹⁷⁷Lu for radionuclide therapy. Furthermore, we combined [¹⁷⁷Lu]Lu-DOTA-CCK₂R-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 [⁶⁸Ga]Ga-DOTA-CCK-66, [⁶⁸Ga]Ga-DOTA-CCK₂R-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, [¹⁷⁷Lu]Lu-DOTA-CCK₂R-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-CCK₂R-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 CCK₂R-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}

{"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@CeO₂) as a novel ferroptosis-targeting therapeutic. <b>Results:</b> DFOM@CeO₂ 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@CeO₂ demonstrated strong antioxidant capacity, effectively reducing iron accumulation and lipid peroxidation, and restoring glutathione peroxidase 4 (GPX4) expression in NP cells. Furthermore, DFOM@CeO₂ improved mitochondrial respiratory chain function, reduce mitochondrial ROS production and prevent mitochondrial dysfunction. In a rat model of IVDD, DFOM@CeO₂ significantly preserved disc height, reduced ECM degradation, and demonstrated superior therapeutic efficacy compared with DFOM or CeO₂ alone. Transcriptome analysis revealed that DFOM@CeO₂ modulates key ferroptosis-related genes and promotes mitochondrial reprogramming. <b>Conclusions:</b> These findings highlight DFOM@CeO₂ 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}