Theranostics最新文献

{"title":"Amide naphthotube as a novel supramolecular sequestration agent for tetracaine and decamethonium","authors":"Cheng-Da Zhao, Wei Cai, Wen-Jie Chen, Huan Yao, Song-Meng Wang, Kailin Li, Yan-Long Ma, Li-Li Wang, Liu-Pan Yang","doi":"10.7150/thno.93654","DOIUrl":"https://doi.org/10.7150/thno.93654","url":null,"abstract":"Rationale: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes./nMethods: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using ¹H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments./nResults: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (<i>K</i>_a = 1.89×10⁷ M^-1) and decamethonium (<i>K</i>_a = 1.01×10⁷ M^-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na⁺ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism./nConclusion: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted degradation of VEGF with bispecific aptamer-based LYTACs ameliorates pathological retinal angiogenesis","authors":"Ping Zhou, Sai Zhang, Lin Li, Renshuai Zhang, Guizhi Guo, Yufei Zhang, Runa Wang, Miaoyuan Liu, Zhiyi Wang, Huijie Zhao, Guiwen Yang, Songbo Xie, Jie Ran","doi":"10.7150/thno.98467","DOIUrl":"https://doi.org/10.7150/thno.98467","url":null,"abstract":"<b>Rationale:</b> Neovascular ocular diseases (NODs) represent the leading cause of visual impairment globally. Despite significant advances in anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF), persistent challenges remain prevalent. As a proof-of-concept study, we herein demonstrate the effectiveness of targeted degradation of VEGF with bispecific aptamer-based lysosome-targeting chimeras (referred to as VED-LYTACs)./n<b>Methods:</b> VED-LYTACs were constructed with three distinct modules: a mannose-6-phosphate receptor (M6PR)-binding motif containing an M6PR aptamer, a VEGF-binding module with an aptamer targeting VEGF, and a linker essential for bridging and stabilizing the two-aptamer structure. The degradation efficiency of VED-LYTACs via the autophagy-lysosome system was examined using an enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. Subsequently, the anti-angiogenic effects of VED-LYTACs were evaluated using <i>in vitro</i> wound healing assay, tube formation assay, three-dimensional sprouting assay, and <i>ex vivo</i> aortic ring sprouting assay. Finally, the potential therapeutic effects of VED-LYTACs on pathological retinal neovascularization and vascular leakage were tested by employing mouse models of NODs./n<b>Results:</b> The engineered VED-LYTACs promote the interaction between M6PR and VEGF, consequently facilitating the translocation and degradation of VEGF through the lysosome. Our data show that treatment with VED-LYTACs significantly suppresses VEGF-induced angiogenic activities both <i>in vitro</i> and<i> ex vivo</i>. In addition, intravitreal injection of VED-LYTACs remarkably ameliorates abnormal vascular proliferation and leakage in mouse models of NODs./n<b>Conclusion:</b> Our findings present a novel strategy for targeting VEGF degradation with an aptamer-based LYTAC system, effectively ameliorating pathological retinal angiogenesis. These results suggest that VED-LYTACs have potential as therapeutic agents for managing NODs.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive ultrasound localization microscopy (ULM) in azoospermia: connecting testicular microcirculation to spermatogenic functions","authors":"Maoyao Li, Xingxuan Zhang, Jipeng Yan, Huiquan Shu, Zitong Li, Chujun Ye, Lei Chen, Chao Feng, Yuanyi Zheng","doi":"10.7150/thno.99668","DOIUrl":"https://doi.org/10.7150/thno.99668","url":null,"abstract":"<b>Rationale:</b> Azoospermia is a significant reproductive challenge. Differentiating between non-obstructive azoospermia (NOA) and obstructive azoospermia (OA) is crucial as each type requires distinct management strategies. Testicular microcirculation plays a profound role in spermatogenic functions. However, current diagnostic methods are limited in their ability to effectively elucidate this crucial connection./n<b>Methods:</b> We employed ultrasound localization microscopy (ULM) to visualize testicular microcirculation in NOA and OA patients and quantified the testicular hemodynamic parameters. Pearson correlation analysis was conducted to investigate the inner connection between parameters of testicular microcirculation and clinical spermatogenic functions. We conducted multiple logistic regression analysis to establish a new diagnostic model that integrates follicle-stimulating hormone (FSH) and mean vascular diameter to distinguish NOA from OA./n<b>Results:</b> Our findings demonstrated significant differences in vascular parameters between NOA and OA, with NOA characterized by lower mean vascular diameter (p &lt; 0.001), vessel density (p &lt; 0.001), and fractal number (p &lt; 0.001). Testicular volume showed a moderate positive correlation with mean vascular diameter (r = 0.419, p &lt; 0.01) and vessel density (r = 0.415, p &lt; 0.01); Mean vascular diameter exhibited negative correlations with both FSH (r = -0.214, p &lt; 0.05) and age (r = -0.240, p &lt; 0.05); FSH (r = -0.202, p &lt; 0.05) and luteinizing hormone (LH) (r = -0.235, p &lt; 0.05) were negatively correlated with mean blood flow velocity. The diagnostic model demonstrated an area under the curve (AUC) of 0.968. We also reported a method to map the vascular pressure distribution derived from the blood flow velocity generated by ULM./n<b>Conclusions:</b> ULM provides a non-invasive and detailed assessment of testicular microvascular dynamics. The ULM-derived vascular parameters are able to connect testicular microcirculation to spermatogenic functions. The combination of FSH and mean vascular diameter enhances diagnostic precision and holds potential for distinguishing NOA from OA.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extrachromosomal circular DNA orchestrates genome heterogeneity in urothelial bladder carcinoma","authors":"Wei Lv, Xiaoguang Pan, Peng Han, Shuang Wu, Yuchen Zeng, Qingqing Wang, Lidong Guo, Mengyang Xu, Yanwei Qi, Li Deng, Zhe Xu, Conghui Li, Tianxi Yu, Xin Cui, Huajing Teng, Chongjun Xiang, Haotian Tan, Yue Li, Ning Liang, Huiying Tao, Qingqing Gao, Guohua Yu, Jia Mi, Fuyi Xu, Benjiao Gong, Lei Shi, Tao Wang, Huanming Yang, Wei Dong, Lars Bolund, Lin Lin, Wenting Wang, Hanbo Li, Jinrong Huang, Chunhua Lin, Yonglun Luo","doi":"10.7150/thno.99563","DOIUrl":"https://doi.org/10.7150/thno.99563","url":null,"abstract":"<b>Rationale:</b> Extrachromosomal circular DNA is a hallmark of cancer, but its role in shaping the genome heterogeneity of urothelial bladder carcinoma (UBC) remains poorly understood. Here, we comprehensively analyzed the features of extrachromosomal circular DNA in 80 UBC patients./n<b>Methods:</b> We performed whole-genome/exome sequencing (WGS/WES), Circle-Seq, single-molecule real-time (SMRT) long-read sequencing of circular DNA, and RNA sequencing (RNA-Seq) on 80 pairs of tumor and AT samples. We used our newly developed circular DNA analysis software, Circle-Map⁺⁺ to detect small extrachromosomal circular DNA from Circle-Seq data./n<b>Results:</b> We observed a high load and significant heterogeneity of extrachromosomal circular DNAs in UBC, including numerous single-locus and complex chimeric circular DNAs originating from different chromosomes. This includes highly chimeric circular DNAs carrying seven oncogenes and circles from nine chromosomes. We also found that large tumor-specific extrachromosomal circular DNAs could influence genome-wide gene expression, and are detectable in time-matched urinary sediments. Additionally, we found that the extrachromosomal circular DNA correlates with hypermutation, copy number variation, oncogene amplification, and clinical outcome./n<b>Conclusions:</b> Overall, our study provides a comprehensive extrachromosomal circular DNA map of UBC, along with valuable data resources and bioinformatics tools for future cancer and extrachromosomal circular DNA research.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Energy level as a theranostic factor for successful therapy of tissue injuries with polyphosphate: the triad metabolic energy - mechanical energy - heat","authors":"Werner E.G. Müller, Hadrian Schepler, Meik Neufurth, Rita Dobmeyer, Renato Batel, Heinz C. Schröder, Xiaohong Wang","doi":"10.7150/thno.100622","DOIUrl":"https://doi.org/10.7150/thno.100622","url":null,"abstract":"<b>Rationale:</b> Tissue regeneration of skin and bone is an energy-intensive, ATP-consuming process that, if impaired, can lead to the development of chronic clinical pictures. ATP levels in the extracellular space including the exudate of wounds, especially chronic wounds, are low. This deficiency can be compensated by inorganic polyphosphate (polyP) supplied <i>via</i> the blood platelets to the regenerating site./n<b>Methods:</b> The contribution of the different forms of energy derived from polyP (metabolic energy, mechanical energy and heat) to regeneration processes was dissected and studied both <i>in vitro</i> and in patients. ATP is generated metabolically during the enzymatic cleavage of the energy-rich anhydride bonds between the phosphate units of polyP, involving the two enzymes alkaline phosphatase (ALP) and adenylate kinase (ADK). Exogenous polyP was administered after incorporation into compressed collagen or hydrogel wound coverages to evaluate its regenerative activity for chronic wound healing./n<b>Results:</b> In a proof-of-concept study, fast healing of chronic wounds was achieved with the embedded polyP, supporting the crucial regeneration-promoting activity of ATP. In the presence of Ca²⁺ in the wound exudate, polyP undergoes a coacervation process leading to a conversion of fibroblasts into myofibroblasts, a crucial step supporting cell migration during regenerative tissue repair. During coacervation, a switch from an endothermic to an exothermic, heat-generating process occurs, reflecting a shift from an entropically- to an enthalpically-driven thermodynamic reaction. In addition, mechanical forces cause the appearance of turbulent flows and vortices during liquid-liquid phase separation. These mechanical forces orient the cellular and mineralic (hydroxyapatite crystallite) components, as shown using mineralizing SaOS-2 cells as a model./n<b>Conclusion:</b> Here we introduce the energetic triad: metabolic energy (ATP), thermal energy and mechanical energy as a novel theranostic biomarker, which contributes essentially to a successful application of polyP for regeneration processes.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bisecting GlcNAc modification reverses the chemoresistance via attenuating the function of P-gp","authors":"Zengqi Tan, Lulu Ning, Lin Cao, Yue Zhou, Jing Li, Yunyun Yang, Shuai Lin, Xueting Ren, Xiaobo Xue, Huafeng Kang, Xiang Li, Feng Guan","doi":"10.7150/thno.93879","DOIUrl":"https://doi.org/10.7150/thno.93879","url":null,"abstract":"<b>Rationale:</b> Chemoresistance is a key factor contributing to the failure of anti-breast cancer chemotherapy. Although abnormal glycosylation is closely correlated with breast cancer progression, the function of glycoconjugates in chemoresistance remains poorly understood./n<b>Methods:</b> Levels and regulatory roles of bisecting N-acetylglucosamine (GlcNAc) in chemoresistant breast cancer cells were determined in vitro and in vivo. Glycoproteomics guided identification of site-specific bisecting GlcNAc on P-glycoprotein (P-gp). Co-immunoprecipitation coupled mass spectrometry (Co-IP-MS) and proximity labelling MS identified the interactome of P-gp, and the biological function of site-specific bisecting GlcNAc was investigated by site/truncation mutation and structural simulations./n<b>Results:</b> Bisecting GlcNAc levels were reduced in chemoresistant breast cancer cells, accompanied by an enhanced expression of P-gp. Enhanced bisecting GlcNAc effectively reversed chemoresistance. Mechanical study revealed that bisecting GlcNAc impaired the association between Ezrin and P-gp, leading to a decreased expression of membrane P-gp. Bisecting GlcNAc suppressed VPS4A-mediated P-gp recruitment into microvesicles, and chemoresistance transmission. Structural dynamics analysis suggested that bisecting GlcNAc at Asn494 introduced structural constraints that rigidified the conformation and suppressed the activity of P-gp./n<b>Conclusion:</b> Our findings highlight the crucial role of bisecting GlcNAc in chemoresistance and suggest the possibility of reversing chemoresistance by modulating the specific glycosylation in breast cancer therapy.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theoretical basis, state and challenges of living cell-based drug delivery systems","authors":"Wei Liu, Guowang Cheng, Hao Cui, Zhen Tian, Bowen Li, Yanhua Han, Jia-Xin Wu, Jie Sun, Yuyue Zhao, Tongkai Chen, Guangtao Yu","doi":"10.7150/thno.99257","DOIUrl":"https://doi.org/10.7150/thno.99257","url":null,"abstract":"The therapeutic efficacy of drugs is determined, to a certain extent, by the efficiency of drug delivery. The low efficiency of drug delivery systems (DDSs) is frequently associated with serious toxic side effects and can even prove fatal in certain cases. With the rapid development of technology, drug delivery has evolved from using traditional frameworks to using nano DDSs (NDDSs), endogenous biomaterials DDSs (EBDDSs), and living cell DDSs (LCDDSs). LCDDSs are receiving widespread attention from researchers at present owing to the unique advantages of living cells in targeted drug delivery, including their excellent biocompatibility properties, low immunogenicity, unique biological properties and functions, and role in the treatment of diseases. However, the theoretical basis and techniques involved in the application of LCDDSs have not been extensively summarized to date. Therefore, this review comprehensively summarizes the properties and applications of living cells, elaborates the various drug loading approaches and controlled drug release, and discusses the results of clinical trials. The review also discusses the current shortcomings and prospects for the future development of LCDDSs, which will serve as highly valuable insights for the development and clinical transformation of LCDDSs in the future.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-purposing disulfiram for enhanced chemotherapy and afterglow imaging using chlorin e6 and semiconducting polymer combined strategy","authors":"Di Zhao, Aifang Zhou, Xintong Dong, Hong-Min Meng, Yating He, Lingbo Qu, Ke Zhang, Yuehe Lin, Zhaohui Li","doi":"10.7150/thno.96136","DOIUrl":"https://doi.org/10.7150/thno.96136","url":null,"abstract":"<b>Rationale:</b> One of the main challenges in chemotherapy is achieving high treatment efficacy while minimizing adverse events. Fully exploiting the therapeutic potential of an old drug and monitoring its effects <i>in vivo</i> is highly valuable, but often difficult to achieve./n<b>Methods:</b> In this study, by encapsulating disulfiram (DSF) approved by US Food and Drug Administration, semiconducting polymer nanocomplex (MEHPPV), and Chlorin e6 into a polymeric matrix F127 via nanoprecipitation method, a nanosystem (FCMC) was developed for afterglow imaging guided cancer treatment. The characteristics, stability as well as the ability of singlet oxygen (¹O₂) production of FCMC were first carefully examined. Then, we studied the mechanism for enhanced anti-cancer efficiency and afterglow luminescence <i>in vitro</i>. For experiments<i> in vivo</i>, 4T1 subcutaneous xenograft tumor mice were injected with FCMC via the tail vein every three days and the antitumor effect of FCMC was evaluated by monitoring tumor volume and body weight every three day./n<b>Results:</b> The nanosystem, which combines DSF with Ce6, can generates abundant ¹O₂ that enhances the antitumor activity of DSF. The <i>in vivo</i> results show that FCMC-treated group exhibits an obviously higher tumor-growth inhibition rate of 67.89% after 15 days of treatment, compared to the control group of F127@MEHPPV-CuET. Moreover, Ce6 also greatly enhances the afterglow luminescence intensity of MEHPPV and promotes the redshift of the afterglow emission towards the ideal near-infrared imaging window, thereby enabling efficient afterglow tumor imaging <i>in vivo</i>./n<b>Conclusions:</b> This multifunctional nanoplatform not only improves the anticancer efficacy of DSF, but also enables monitoring tumor via robust afterglow imaging, thus exhibiting great potential for cancer therapy and early therapeutic outcome prediction.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>DAB2</i> ⁺ macrophages support <i>FAP</i> ⁺ fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.","authors":"Fei Long, Wei Zhong, Faming Zhao, Yaqi Xu, Xin Hu, Gaihua Jia, Lanxiang Huang, Kezhen Yi, Na Wang, Huaqi Si, Jun Wang, Bicheng Wang, Yuan Rong, Yufeng Yuan, Chunhui Yuan, Fubing Wang","doi":"10.7150/thno.99046","DOIUrl":"10.7150/thno.99046","url":null,"abstract":"<p><p><b>Background:</b> Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. <b>Methods:</b> A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. <b>Results:</b> Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). <i>FAP</i> ⁺ fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The <i>DAB2</i> ⁺ and <i>SPP1</i> ⁺ tumor-associated macrophages (TAMs) reinforce the function of <i>FAP</i> ⁺ CAFs through signals such as TGF-β, PDGF, and ADM. Notably, the interaction between <i>DAB2</i> ⁺ TAMs and <i>FAP</i> ⁺ CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. <b>Conclusions:</b> The interaction between <i>DAB2</i> ⁺ TAMs and <i>FAP</i> ⁺ CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of <i>FAP</i> ⁺ CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141143","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":"Brain-targeted intranasal delivery of protein-based gene therapy for treatment of ischemic stroke.","authors":"Jee-Yeon Ryu, Christian Cerecedo-Lopez, Hongkuan Yang, Ilhwan Ryu, Rose Du","doi":"10.7150/thno.98088","DOIUrl":"10.7150/thno.98088","url":null,"abstract":"<p><p>Gene therapy using a protein-based CRISPR system in the brain has practical limitations due to current delivery systems, especially in the presence of arterial occlusion. To overcome these obstacles and improve stability, we designed a system for intranasal administration of gene therapy for the treatment of ischemic stroke. <b>Methods:</b> Nanoparticles containing the protein-based CRISPR/dCas9 system targeting <i>Sirt1</i> were delivered intranasally to the brain in a mouse model of ischemic stroke. The CRISPR/dCas9 system was encapsulated with calcium phosphate (CaP) nanoparticles to prevent them from being degraded. They were then conjugated with β-hydroxybutyrates (bHb) to target monocarboxylic acid transporter 1 (MCT1) in nasal epithelial cells to facilitate their transfer into the brain. <b>Results:</b> Human nasal epithelial cells were shown to uptake and transfer nanoparticles to human brain endothelial cells with high efficiency <i>in vitro</i>. The intranasal administration of the dCas9/CaP/PEI-PEG-bHb nanoparticles in mice effectively upregulated the target gene, <i>Sirt1</i>, in the brain, decreased cerebral edema and increased survival after permanent middle cerebral artery occlusion. Additionally, we observed no significant <i>in vivo</i> toxicity associated with intranasal administration of the nanoparticles, highlighting the safety of this approach. <b>Conclusion:</b> This study demonstrates that the proposed protein-based CRISPR-dCas9 system targeting neuroprotective genes in general, and <i>SIRT1</i> in particular, can be a potential novel therapy for acute ischemic stroke.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141148","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}