Theranostics最新文献

{"title":"Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.","authors":"Keqiang Zhang, Ching Ouyang, Jonathan Castillo, Jinhui Wang, Walter Tsark, Yuanyuan Gao, Wendong Li, Minxiao Yang, Aimin Li, Britney Oeung, Colt Egelston, Jun Wu, Mahima Raul, Leonidas Arvanitis, Crystal Marconett, Dan J Raz","doi":"10.7150/thno.125898","DOIUrl":"10.7150/thno.125898","url":null,"abstract":"<p><strong>Rationale: </strong>Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the \"Death-from-Cancer\" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer.</p><p><strong>Methods: </strong>A conditional Usp22 knockout (Usp22-KO) was generated in the KRAS^G12D; p53^-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers.</p><p><strong>Results: </strong>USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers.</p><p><strong>Conclusions: </strong>USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8708-8732"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907271","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":"An integrated SOX4-driven transcriptional and metabolic program governs tumor-infiltrating regulatory T cells in ovarian cancer.","authors":"Lei Wu, Ziqi Tao, Yuelu Zhang, Yepeng Mao, Lei Zhang, Lina Yan, Rong Li, Lingfei Zhou, Zhijie Liu, Wenwen Shang, Shuna Liu, Jianfang Lou, Xi Huang, Ting Wang, Fang Wang","doi":"10.7150/thno.131793","DOIUrl":"10.7150/thno.131793","url":null,"abstract":"<p><strong>Background: </strong>Regulatory T cells (Tregs) suppress antitumor immunity in ovarian cancer (OC) and are promising targets for immunotherapy. However, the heterogeneity and regulatory mechanisms of tumor-infiltrating Tregs (TI-Tregs) remain poorly defined. Here, we aim to delineate TI-Treg programs to identify potential therapeutic targets.</p><p><strong>Methods: </strong>CD4⁺CD25⁺CD127⁻ Tregs from OC, adjacent tissues, and peripheral blood were profiled by single-cell RNA sequencing and spatial transcriptomics, with regulatory networks inferred using SCENIC. Functional and mechanistic studies of SOX4 were performed using hypoxic/tumor-conditioned models, CRISPR-Cas9 perturbation, ectopic overexpression, Cut&Tag profiling, and oxidative phosphorylation (OXPHOS) inhibition.</p><p><strong>Results: </strong>We identified nine transcriptionally distinct Treg subsets, revealing a highly activated and immunosuppressive state among TI-Tregs. These TI-Tregs exhibited strong co-expression of <i>TNFRSF4</i>, <i>TNFRSF9</i>, <i>TNFRSF18</i>, and <i>CTLA4</i>, and their increased intratumoral abundance was independently associated with poorer overall survival. SCENIC analysis identified SOX4 as the top regulon defining TI-Treg identity, with spatial transcriptomics revealing SOX4⁺ Tregs forming an immunoregulatory barrier at tumor margins. This phenotypic identity was robustly induced by the hypoxic microenvironment and TCR stimulation in a well-established murine OC model. Mechanistically, SOX4 transactivated MT1X to promote mitochondrial fitness and OXPHOS. Consistently, Cut&Tag profiling showed reduced chromatin accessibility at OXPHOS-related loci following SOX4 depletion. Furthermore, CRISPR-Cas9-mediated disruption of SOX4 reduced FOXP3 expression and other suppressive markers, whereas SOX4 overexpression enhanced FOXP3 expression in an OXPHOS-dependent manner. Notably, pharmacological inhibition of OXPHOS abolished this effect.</p><p><strong>Conclusions: </strong>SOX4 is a central regulator of TI-Treg suppressive function and metabolic fitness, representing a promising therapeutic target for OC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8611-8632"},"PeriodicalIF":14.9,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906437","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":"Focused ultrasound-mediated blood-brain barrier modulation is associated with adult hippocampal neurogenic responses linked to zinc-dependent signaling.","authors":"Bo Young Choi, Jaewoo Shin, Chanho Kong, Min Kyu Park, Dae Ki Hong, Young-Soo Chung, Sang Won Suh, Won Seok Chang","doi":"10.7150/thno.133902","DOIUrl":"10.7150/thno.133902","url":null,"abstract":"<p><strong>Rationale: </strong>Transcranial focused ultrasound (FUS)-mediated blood-brain barrier (BBB) modulation is a promising non-invasive therapeutic strategy for targeted brain drug delivery. However, its direct regenerative potential to actively remodel the brain microenvironment and promote adult hippocampal neurogenesis remains largely unexplored owing to elusive molecular mediators. Here, we investigated whether zinc-dependent signaling contributes to adult hippocampal neurogenic responses following FUS-mediated BBB modulation.</p><p><strong>Methods: </strong>We integrated pharmacological and genetic approaches in adult rodent models subjected to hippocampal-targeted low-intensity FUS with microbubbles. Neural progenitor proliferation and differentiation were quantified using BrdU and DCX labeling. To assess the contributions of extracellular/labile zinc availability and ZnT3-associated vesicular zinc physiology, intracerebroventricular zinc chelation with CaEDTA was performed in rats, and ZnT3^-/- mice were used. Molecular assays and exploratory bulk RNA sequencing were conducted to characterize candidate downstream molecular pathways.</p><p><strong>Results: </strong>FUS-mediated BBB modulation significantly increased dentate gyrus progenitor proliferation, neuroblast abundance, and newborn neuron survival. These effects were markedly attenuated by acute zinc chelation and were not observed in ZnT3^-/- mice, indicating that intact zinc availability and ZnT3-associated zinc physiology are required for the full FUS-associated neurogenic response. FUS was associated with increased expression of brain-derived neurotrophic factor, Zrt-/Irt-like protein 3 (ZIP-3), and Piezo1 proteins, and zinc chelation attenuated these increases. ZIP-3 and Piezo1 signals overlapped with NeuN-positive cells, suggesting neuronal enrichment. In addition, exploratory bulk transcriptomic profiling of whole hippocampal tissue revealed candidate signatures associated with neurovascular and glial responses following FUS in ZnT3⁺/⁺ mice, whereas the corresponding transcriptomic responses appeared reduced or altered in ZnT3^-/- mice.</p><p><strong>Conclusions: </strong>Our findings support a framework in which intact zinc availability, including ZnT3-associated zinc physiology, contributes to adult hippocampal neurogenic responses following FUS-mediated BBB modulation. This work provides a mechanistic framework for the development of ultrasound-guided therapeutic strategies aimed at promoting repair-associated plasticity in neurological disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8561-8579"},"PeriodicalIF":14.9,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907200","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":"Erratum: Co-delivery of siPTPN13 and siNOX4 <i>via</i> (myo)fibroblast-targeting polymeric micelles for idiopathic pulmonary fibrosis therapy: Erratum.","authors":"Jiwei Hou, Qijian Ji, Jie Ji, Shenghong Ju, Chun Xu, Xueqing Yong, Xiaoxuan Xu, Mohd Muddassir, Xiang Chen, Jinbing Xie, Xiaodong Han","doi":"10.7150/thno.137233","DOIUrl":"https://doi.org/10.7150/thno.137233","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.7150/thno.54217.].</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8559-8560"},"PeriodicalIF":14.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907198","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":"Novel nastorazepide-based radioligands demonstrate effective cholecystokinin-2 receptor targeting with potential for theranostic applications.","authors":"Lennart Bohrmann, Doroteja Novak, Marko Kroselj, Raghuvir H Gaonkar, Francesca Porto, Melpomeni Fani, Petra Kolenc, Marko Anderluh, Rosalba Mansi","doi":"10.7150/thno.129327","DOIUrl":"10.7150/thno.129327","url":null,"abstract":"<p><p>Radiolabeled gastrin antagonists are emerging as a new tool for the diagnosis and treatment of cholecystokinin-2 receptor (CCK2R) expressing tumors such as medullary thyroid carcinoma and small cell lung cancer, overcoming limitations of agonist-based ligands. In this study, the CCK2R antagonist nastorazepide (Z-360) was used as a targeting scaffold in combination with either a peptidic (NPP) or a hydrophilic polysaccharide (NPS) linker and the chelators DOTA and DOTAGA, yielding four novel radioligands. These were evaluated alongside the reference minigastrin analogs DOTA-PP-F11 and DOTA-MGS5.</p><p><strong>Methods: </strong>All ligands were synthetized <i>via</i> solid-phase peptide synthesis and labeled with In-111 and Lu-177. <i>In vitro</i> characterization included receptor affinity, hydrophilicity and cellular uptake in A431-CCK2R. <i>In vivo</i> biodistribution and imaging were performed in A431-CCK2R xenografts. [¹⁷⁷Lu]Lu-DOTAGA-NPP was further assessed in a proof-of-concept therapy study and metabolic stability assays.</p><p><strong>Results: </strong>¹¹¹In-labeled antagonists showed 3-4-fold higher site recognition than [¹¹¹In]In-DOTA-PP-F11 and nanomolar affinities comparable to the reference ligand. Among the tested ligands, [¹¹¹In]In-DOTAGA-NPP demonstrated the highest cellular uptake (22.0 ± 0.2%), approximately twice that of the other ligands and moderately higher than [¹¹¹In]In-DOTA-PP-F11 (16.2 ± 1.8%) after 4 h at 37 °C. <i>In vivo</i>, all ¹⁷⁷Lu-labeled antagonists demonstrated high tumor uptake (range: 22.98 ± 7.04 - 29.00 ± 3.30% I.A./g tissue) with [¹⁷⁷Lu]Lu-DOTAGA-NPP exhibiting the most favorable tumor-to-tissue ratios. Compared with [¹⁷⁷Lu]Lu-DOTA-MGS5, [¹⁷⁷Lu]Lu-DOTAGA-NPP showed rapid tumor accumulation with faster washout but reduced stomach exposure and high <i>in vivo</i> stability.</p><p><strong>Conclusion: </strong>[¹⁷⁷Lu]Lu-DOTAGA-NPP emerged as the most promising lead compound, combining high tumor uptake, favorable tumor-to-organ ratios, and excellent <i>in vivo</i> stability. Although no significant therapeutic efficacy was observed in the tested xenograft model, the results support [¹⁷⁷Lu]Lu-DOTAGA-NPP as a promising lead for optimization. Overall, these findings highlight the potential of Z-360-based CCK2R antagonists as scaffolds for next-generation theranostic radioligands and support their development as alternatives to minigastrin-based tracers.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8447-8460"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907244","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 multimodal pipeline for the identification and diagnostic immunoPET validation of hepatocellular carcinoma targets for radiotheranostic development.","authors":"Philip Homan, Joon-Yong Chung, Woonghee Lee, Divya Nambiar, Julia Sheehan-Klenk, Hima Makala, Stanley Fayn, Orit Jacobson, Arthur Paden King, Kyungeun Kim, Jeong Won Kim, Sung Ryol Lee, Maggie Cam, Stephen M Hewitt, Xin Wei Wang, Mitchell Ho, Freddy E Escorcia","doi":"10.7150/thno.136906","DOIUrl":"10.7150/thno.136906","url":null,"abstract":"<p><strong>Background: </strong>Identifying tumor selective targets is critical for the development of precision diagnostic and therapeutic agents in oncology. Despite advances in precision oncology elsewhere, there are no FDA-approved hepatocellular carcinoma (HCC) antigen-selective antibody-drug conjugates or radiopharmaceuticals. This study establishes an integrated workflow to identify HCC-enriched plasma membrane targets and assess their suitability for targeted molecular imaging as foundational candidates for future radiopharmaceutical therapy.</p><p><strong>Methods: </strong>Bulk RNA sequencing (371 tumors), single cell RNA sequencing (34 HCC cases), and a normal liver dataset were analyzed to identify HCC-enriched plasma membrane targets. Candidate molecules were examined on HCC and normal tissue microarrays (TMAs) and further evaluated in liver cancer cell lines by quantitative PCR, Western blot, and flow cytometry. Selected targets were then tested in mouse models of liver cancer using antibody-based positron emission tomography (immunoPET) to assess <i>in vivo</i> target engagement and distribution.</p><p><strong>Results: </strong>Integrated transcriptomic analysis identified several tumor plasma membrane molecules with strong tumor enrichment, including GPC3, MUC13, TSPAN8, MET, and EGFR. TMAs confirmed prominent membrane expression in HCC with little signal in normal organs. Combinations of four prioritized markers captured up to 88.5% of patient tumors. Antibody-based immunoPET agents directed against prioritized targets demonstrated specific tumor accumulation <i>in vivo</i>, and signal intensity correlated with membrane staining by immunohistochemistry. These results highlight the potential of these markers to serve as diagnostic tools and promising candidate platforms for therapeutic development, demonstrating the utility of this approach to identify novel oncology targets.</p><p><strong>Conclusions: </strong>This study establishes a multimodal framework integrating transcriptomic predictions and experimental protein validation to identify HCC targets for molecular imaging and radiopharmaceutical development. This translational blueprint successfully advances precision diagnostic and theranostic-ready agents for this disease for HCC, and a similar approach may be useful for identifying and validating targets in other malignancies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8501-8520"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-metallic porphyrinic MOFs with pH/ROS-responsive release for antibacterial and antioxidant therapy of diabetic infected wounds.","authors":"Yipeng Pang, Fructueux Modeste Amona, Hanyuan Liu, Shuming Tang, Jianlong Lao, Xi Chen, Xiaoye Wang","doi":"10.7150/thno.135365","DOIUrl":"10.7150/thno.135365","url":null,"abstract":"<p><strong>Rationale: </strong>Chronic diabetic wounds are complicated by multidrug-resistant (MDR) infections and a deleterious oxidative microenvironment, rendering single-target therapies ineffective. This study aimed to develop a smart, dual-metal-organic framework (MOF) nanoplatform (PCNZnCy) capable of microenvironment-responsive, coordinated antibacterial, antioxidant, and pro-regenerative therapy for infected diabetic wounds.</p><p><strong>Methods: </strong>The nanoplatform PCNZnCy was constructed by integrating the natural flavonoid chrysin into a zinc-doped porphyrinic MOF (PCN-224), enabling pH- and reactive oxygen species (ROS)-triggered co-release of Zn²⁺ and chrysin. Antibacterial and anti-biofilm activity was assessed against biofilm-embedded MDR pathogens, including methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and <i>Pseudomonas aeruginosa</i> (PA). Antioxidant and signaling effects were evaluated by measuring ROS scavenging, mitochondrial function, endothelial cell proliferation, and activation of Nrf2/HO-1, STAT3, and Akt pathways, with confirmation using the Nrf2 inhibitor ML385. To assess efficacy and safety in a clinically meaningful setting, we used a diabetic murine wound model infected with <i>P. aeruginosa</i> and a systems-level transcriptomic analysis to capture the broader tissue response.</p><p><strong>Results: </strong>We found that PCNZnCy showed strong synergistic antibacterial activity against MRSA and PA. Beyond that, it scavenged excess ROS, triggered Nrf2/HO-1 signaling, modulated STAT3 and Akt signaling, preserved mitochondrial health, and spurred endothelial cell growth. In diabetic mice, wounds healed faster, with improved collagen deposition and increased formation of new blood vessels, while the compound remained safe. RNA-seq data underscored a decisive move from pro-inflammatory to pro-regenerative gene expression.</p><p><strong>Conclusions: </strong>PCNZnCy adapts to the wound's specific microenvironment, enabling it to kill bacteria, reduce oxidative stress, and promote tissue regeneration. In the infected diabetic models, it worked consistently well. This makes it a strong candidate for multifactorial, complex wound pathologies, in which multiple complications overlap.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8521-8545"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907022","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":"Frailty and [¹⁷⁷Lu]Lu-PSMA-617 therapy: tools and strategies for older men with metastatic castration-resistant prostate cancer.","authors":"Matteo Bauckneht, Nicolò Borsellino, Giuseppe Ferdinando Colloca, Lucia Fratino, Daniele Santini","doi":"10.7150/thno.131438","DOIUrl":"10.7150/thno.131438","url":null,"abstract":"<p><p>The prognosis of metastatic castration-resistant prostate cancer is dismal. [¹⁷⁷Lu]Lutetium-prostate-specific membrane antigen (PSMA)-617 ([¹⁷⁷Lu]Lu-PSMA-617) is the new standard of care for PSMA-positive mCRPC previously treated with ARPI and taxane-based chemotherapy. The efficacy and safety of [¹⁷⁷Lu]Lu-PSMA-617 have been confirmed by phase 2 (TheraP [NCT03392428]) and phase 3 (VISION study [NCT02511664] and PSMAfore trial [NCT04689828]) clinical trials. A substantial proportion of patients with mCRPC are older adults; however, chronological age alone should not be considered a contraindication to [¹⁷⁷Lu]Lu-PSMA-617 therapy. Instead, therapeutic decisions must be guided by a comprehensive evaluation of life expectancy, comorbidities, and frailty. Here we review the effectiveness and safety data for [¹⁷⁷Lu]Lu-PSMA-617, present tools for the geriatric and frailty assessments in clinical practice and discuss its utility and therapeutic indications in patients with different types of frailty.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 15","pages":"8546-8558"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907150","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":"miR-15a-5p outperforms anti-VEGF drug in ocular neovascularization by providing dual anti-angiogenic and neuroprotective effects.","authors":"Hui Zhang, Xinyue Yu, Fuhua Yang, Rongguo Yu, Liangzhang Tan, Jinying An, Huan Wang, Yiran Cui, Wenrui Linghu, Yue Wang, Jiahui Wu, Xiaomin Zhang, Xiaorong Li","doi":"10.7150/thno.134644","DOIUrl":"10.7150/thno.134644","url":null,"abstract":"<p><strong>Background: </strong>Pathological ocular neovascularization is a major driver of vision-threatening retinal diseases. This study aimed to investigate the role and therapeutic potential of miR-15a-5p in ocular neovascular disorders.</p><p><strong>Methods: </strong>miR-15a-5p expression levels were assessed in intraocular fluids from patients with ocular neovascular diseases. Functional assays were performed in retinal endothelial cells under pathological conditions to evaluate proliferation and endothelial-to-mesenchymal transition. <i>In vivo</i>, miR-15a-5p was delivered via intravitreal injection in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mouse models. Therapeutic effects on pathological neovascularization were analyzed and compared with anti-VEGF treatment, including assessments of retinal structural integrity, retinal function, gliosis, and fibrotic changes. miR-15a-5p-knockout mice were used to examine retinal vascular developmental abnormalities and enhanced neovascular responses following miR-15a-5p deficiency. Safety evaluations of systemic and ocular administration were performed in both healthy and neovascularized mice. Mechanistic studies investigated whether miR-15a-5p directly targeted VEGF and Smad2.</p><p><strong>Results: </strong>miR-15a-5p was significantly upregulated in intraocular fluids from patients with ocular neovascular diseases. Overexpression of miR-15a-5p inhibited retinal endothelial cell proliferation and endothelial-to-mesenchymal transition <i>in vitro</i>. In OIR and CNV models, miR-15a-5p treatment reduced retinal neovascularization, decreased reactive gliosis, and maintained retinal thickness and electrophysiological function. In miR-15a-5p-knockout mice, loss of miR-15a-5p impaired normal retinal vascular development. Mechanistically, miR-15a-5p directly targeted VEGF and Smad2, modulating angiogenic and fibrotic pathways. Compared with anti-VEGF therapy, miR-15a-5p demonstrated stronger anti-fibrotic and neuroprotective effects without affecting postnatal development or systemic metabolism. No ocular or systemic toxicity was observed at therapeutic doses.</p><p><strong>Conclusions: </strong>miR-15a-5p regulates angiogenesis and fibrosis by targeting VEGF and Smad2. These findings suggest that miR-15a-5p is a promising therapeutic candidate for the treatment of ocular neovascular diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8427-8446"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679678","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 mechanobiology-driven cell-derived ECM bioink for engineering 3D glioblastoma tumor microenvironment models.","authors":"Seohyeon An, Seoyul Jo, GeunHyung Kim","doi":"10.7150/thno.137729","DOIUrl":"10.7150/thno.137729","url":null,"abstract":"<p><p>Glioblastoma (GBM) is highly aggressive and difficult to treat, partly due to the lack of <i>in vitro</i> models that faithfully recapitulate its biochemical and mechanobiological microenvironment. Synthetic hydrogels lack tumor-specific cues, while animal-derived dECM suffers from batch variability, limiting standardization.</p><p><strong>Methods: </strong>Here, we describe a GBM-derived dECM bioink formulated through mechanically stimulated 3D GBM culture within GelMA/HAMA hydrogels. By controlling the matrix stiffness to match GBM tissue and applying various compressive stresses that mimic intracranial solid stress, we identified a mechanobiological activation range that maximized secretion of GBM-associated factors, including GDF15, MMP2, and MMP9.</p><p><strong>Results: </strong>The resulting bioink exhibited upregulated tumor-specific biochemical signals compared to hydrogel-only controls. Micromesh-bioprinted GBM constructs fabricated from this bioink demonstrated enhanced proliferation, invasion-related gene expression, and ECM remodeling. Co-culture with endothelial cells or fibroblasts further reconstructed stromal activation, paracrine signaling, and matrix dynamics associated with GBM progression and therapeutic resistance.</p><p><strong>Conclusion: </strong>This strategy establishes a reproducible, bioactive GBM-specific bioink platform for physiologically relevant 3D GBM modeling and GBM-on-chip applications.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8361-8384"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680030","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}