Laura Pineiro-Alonso, Inés Rubio-Prego, Alexandra Lobyntseva, Eva González-Freire, Robert Langer, María José Alonso
{"title":"Nanomedicine for targeting brain Neurodegeneration: Critical barriers and circadian rhythm Considerations","authors":"Laura Pineiro-Alonso, Inés Rubio-Prego, Alexandra Lobyntseva, Eva González-Freire, Robert Langer, María José Alonso","doi":"10.1016/j.addr.2025.115606","DOIUrl":"https://doi.org/10.1016/j.addr.2025.115606","url":null,"abstract":"The development of novel therapies for central nervous system (CNS) diseases, particularly neurodegenerative disorders like Alzheimer’s disease (AD), is a critical global health priority. Biotherapeutics, such as monoclonal antibodies (mAbs) and RNA-based therapies, have shown potential for treating brain disorders. However, their clinical progress is limited by their difficult access to their brain targets. At the preclinical level, nanotechnology has been shown, to help these molecules overcome the biological barriers that imped their adequate brain delivery. This review highlights advances in this area and the challenges for the translation to the clinic. Key nanotechnology-based strategies, such as surface modifications utilizing endogenous protein corona, functionalization with targeting ligands, therapeutic ultrasound-mediated microbubble oscillation were particularly analyzed. Additionally, in line with the focus of the Special Issue, this review integrates the concept of chronotherapy, with a focus on AD treatment, highlighting the idea that, by aligning nanoparticle (NP)-based drug delivery with circadian rhythms, it may be possible to improve therapeutic outcomes. Finally, the article analyzes current strategies in CNS drug delivery in clinical trials and provides future directions within this frame, notably in the area of AD.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"125 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066511","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}
William Parker, Amanda Taylor, Aryan Razdan, Jose Escarce, Nathan Crook
{"title":"Enabling technologies for in situ biomanufacturing using probiotic yeast","authors":"William Parker, Amanda Taylor, Aryan Razdan, Jose Escarce, Nathan Crook","doi":"10.1016/j.addr.2025.115605","DOIUrl":"https://doi.org/10.1016/j.addr.2025.115605","url":null,"abstract":"<em>Saccharomyces boulardii</em> (<em>Sb</em>) is a Generally Regarded As Safe (GRAS) probiotic yeast currently used to alleviate symptoms from various gastrointestinal diseases. <em>Sb</em> is a promising platform for probiotic and biotherapeutic engineering as it is the only probiotic eukaryote and carries with it a unique set of advantages compared to bacterial strains, including resistance to phage, high protein secretion abilities, and intrinsic resistance to antibiotics. While engineered <em>Sb</em> has not been studied as extensively as its close relative <em>Saccharomyces cerevisiae</em> (<em>Sc</em>), many genetic engineering tools developed for <em>Sc</em> have also shown promise in <em>Sb</em>. In this review, we address recent research to develop tools for genetic engineering, colonization modulation, biomarker sensing, and drug production in <em>Sb</em>. Ongoing efforts, especially those that overcome gut-specific challenges to engineered performance, are highlighted as they advance this chassis as a scalable platform for treating gastrointestinal diseases.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"40 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067294","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}
Ajoa J. Addae, Jennifer Uyanga, Joey Chifamba, Paul S. Weiss
{"title":"Advances in enhancing photoprotection of sunscreens using hydrocarbon film formers and carbon nanomaterials","authors":"Ajoa J. Addae, Jennifer Uyanga, Joey Chifamba, Paul S. Weiss","doi":"10.1016/j.addr.2025.115607","DOIUrl":"https://doi.org/10.1016/j.addr.2025.115607","url":null,"abstract":"Recent developments in sunscreen formulations have been made to enhance sunscreen films formed on the surface of the skin. Film formation is of particular interest for sunscreens because the ability of solubilized ultraviolet (UV) filters to adhere to the skin’s surface in such a way that they efficiently absorb UV light is a significant determinant of sun protection factor (SPF) value. Additionally, methods of stabilizing sunscreen films at the formulation level are of interest due to the degradation of sunscreen on skin-like substrates overtime. We note that traditional solvent-based spectroscopic methods of measuring sunscreens’ efficacy capture only a portion of the story when it comes to determining SPF value and photoprotective properties of sunscreens on human skin. In this forward-looking review, we highlight strategies for enhancing film formation in sunscreens using hydrocarbon film formers and carbon nanomaterials. We discuss challenges of maintaining adhesion of sunscreen films on skin-like substrates, outline properties of hydrocarbon film formers and carbon nanomaterials for improving photoprotection, and present best practices for analyzing sunscreen films at the formulation level. Overall, this review provides insights relevant for sunscreen formulators and clinicians who develop and evaluate sunscreen efficacy.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"52 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945753","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":"Advances in photoactivated carbon-based nanostructured materials for targeted cancer therapy","authors":"Maryam Eftekharifar, Reza Heidari, Neda Mohaghegh, Alireza Hassani Najafabadi, Hossein Heidari","doi":"10.1016/j.addr.2025.115604","DOIUrl":"https://doi.org/10.1016/j.addr.2025.115604","url":null,"abstract":"In this review, we explore key innovations in photoactivated therapeutic programming of carbon-based nanomaterials (CBNs), focusing on their diverse nanostructural configurations and their exceptional photothermal, photochemical, and photoacoustic properties. These attributes position CBNs as remarkable phototherapeutic agents, capable of addressing critical challenges in targeted cancer therapy through their precision, multifunctionality, and adaptability to specific therapeutic modalities. We will explore their diverse derivatives, and the role of chemical augmentation and site-specific surface functionalisation, which are pivotal in optimising the targeting and efficacy of phototherapeutic interventions. The biological and physical relevance of this ever-growing library of nanomaterials in targeted phototherapy will be thoroughly explored. Dynamic photo-triggering of the underlying molecular mechanisms of action e.g., energy conversion modalities lie at the heart of these therapeutic innovations. We will further discuss the tunability and programming of these carriers and structure–function alterations at specific therapeutic wavelengths. The application space of phototherapies is thoroughly mapped exploring the three primary approaches of photothermal therapy, photodynamic therapy and photochemical internalisation as well as emerging techniques and promising multimodal approaches that combine two or more of these processes. The specificity of the target tissue site and the approach under study forms another critical focus area of this review, with an emphasis on three types of cancer—breast cancer, lung cancer, and gliomas—that have demonstrated some of the most promising outcomes from photomedicine. We also provide a perspective on <em>in vitro</em> and <em>in vivo</em> validation and preclinical testing of CBNs for phototherapeutic applications. Finally, we reflect on the potential of CBNs to revolutionise targeted cancer therapy through data-driven materials design and integration with computational tools for biophysical performance optimisation. The exciting integration of machine learning into nanoparticle research and phototherapy has potential to fundamentally transform the landscape of nanomedicine. These techniques ranging from supervised learning algorithms such as random forests and support vector machines to more advanced neural networks and deep learning, can enable unprecedented precision in predicting, optimising, and tailoring the properties of nanoparticles for targeted applications. The transformative impact of photoactivated CBNs in advancing cancer treatment, paves the way for their clinical application and widespread adoption in personalised photomedicine. We conclude with a section on the current challenges facing the reproducibility, manufacturing throughput, and biocompatibility of these nanostructured materials including their long-term effects in trials and degradation profiles in biological systems as evaluated <em>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"32 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932573","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}
Hitesh P. Gelli , Ruben Vazquez-Uribe , Stephen T. Buckley , Jan Terje Andersen , Morten Otto Alexander Sommer
{"title":"Advanced microbiome therapeutics for oral delivery of peptides and proteins: Advances, challenges, and opportunities","authors":"Hitesh P. Gelli , Ruben Vazquez-Uribe , Stephen T. Buckley , Jan Terje Andersen , Morten Otto Alexander Sommer","doi":"10.1016/j.addr.2025.115603","DOIUrl":"10.1016/j.addr.2025.115603","url":null,"abstract":"<div><div>Peptide and protein medicines have changed the therapeutic landscape for many diseases, yet oral delivery remains a significant challenge due to enzymatic degradation, instability, and poor permeability in the gastrointestinal tract. Advanced Microbiome Therapeutics (AMTs) could overcome some of these barriers by producing and releasing therapeutic peptides directly in the gastrointestinal tract. AMTs can localize peptide production at the site of absorption, providing either sustained or controlled release while potentially reducing side effects associated with systemic administration. Here, this review assesses the status of AMTs for oral peptide delivery and discusses the potential integration of permeation enhancers, mucoadhesive systems, and receptor-mediated transport strategies to improve oral bioavailability further. Combining these approaches could pave the way for more widespread oral delivery strategies for peptide and protein medicines.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"222 ","pages":"Article 115603"},"PeriodicalIF":15.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927167","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}
Dingcheng Zhu , Dennis Brückner , Martin Sosniok , Marvin Skiba , Neus Feliu , Marta Gallego , Yang Liu , Florian Schulz , Gerald Falkenberg , Wolfgang J. Parak , Carlos Sanchez-Cano
{"title":"Size-dependent penetration depth of colloidal nanoparticles into cell spheroids","authors":"Dingcheng Zhu , Dennis Brückner , Martin Sosniok , Marvin Skiba , Neus Feliu , Marta Gallego , Yang Liu , Florian Schulz , Gerald Falkenberg , Wolfgang J. Parak , Carlos Sanchez-Cano","doi":"10.1016/j.addr.2025.115593","DOIUrl":"10.1016/j.addr.2025.115593","url":null,"abstract":"<div><div>The penetration of nanoparticle (NP)-based drugs into tissue is essential for their use as nanomedicines. Systematic studies about how different NP properties, such as size, influence NP penetration are helpful for the development of NP-based drugs. An overview of how NPs of different sizes may penetrate three-dimensional cell spheroids is given. In particular different techniques for experimental analysis are compared, including mass spectrometry, flow cytometry, optical fluorescence microscopy, X-ray fluorescence microscopy, and transmission electron microscopy. An experimental data set is supplemented exclusively made for this review, in which the results of different techniques are visualized. Limitations of the analysis techniques for different types of NPs, including carbon-based materials, are discussed.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"222 ","pages":"Article 115593"},"PeriodicalIF":15.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915491","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}
E.Coulter Montague , Bilgehan Ozcan , Elana Sefton , Fanny Wulkan , Faisal J. Alibhai , Michael A. Laflamme
{"title":"Human pluripotent stem cell-based cardiac repair: Lessons learned and challenges ahead","authors":"E.Coulter Montague , Bilgehan Ozcan , Elana Sefton , Fanny Wulkan , Faisal J. Alibhai , Michael A. Laflamme","doi":"10.1016/j.addr.2025.115594","DOIUrl":"10.1016/j.addr.2025.115594","url":null,"abstract":"<div><div>The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and hPSC-derived cardiac progenitors (hPSC-CPs) represents a promising strategy for regenerating hearts damaged by myocardial infarction (MI). After nearly two decades of experience testing these cell populations in various small- and large-animal MI models, multiple clinical trials have recently been initiated. In this review, we consider the principal lessons learned from preclinical experience with hPSC-CMs and -CPs, focusing on three conclusions that have been supported by the majority of reported transplantation studies. First, hPSC-CMs and -CPs stably engraft in injured hearts and partially remuscularize the infarct scar, but more progress is needed to improve graft cell retention and survival. Second, the transplantation of hPSC-CMs and -CPs has been found to improve contractile function in infarcted hearts, but the mechanistic basis for these effects remains incompletely elucidated. Third, the graft tissue formed by these cells can integrate and activate synchronously with host myocardium, but this capacity for electromechanical integration has been associated with an elevated risk of graft-related arrhythmias. Here, we summarize the preclinical evidence supporting these three observations, identify the relevant gaps and barriers to translation, and summarize ongoing efforts to improve the safety and efficacy of hPSC-CM- and -CP-based regenerative therapies.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"222 ","pages":"Article 115594"},"PeriodicalIF":15.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905543","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}
Zahra Rezaei , Niyou Wang , Yipei Yang , Kannan Govindaraj , Jose Joaquin Velasco , Alvaro Dario Martinez Blanco , Nam Ho Bae , HeaYeon Lee , Su Ryon Shin
{"title":"Enhancing organoid technology with carbon-based nanomaterial biosensors: Advancements, challenges, and future directions","authors":"Zahra Rezaei , Niyou Wang , Yipei Yang , Kannan Govindaraj , Jose Joaquin Velasco , Alvaro Dario Martinez Blanco , Nam Ho Bae , HeaYeon Lee , Su Ryon Shin","doi":"10.1016/j.addr.2025.115592","DOIUrl":"10.1016/j.addr.2025.115592","url":null,"abstract":"<div><div>Various carbon-based nanomaterials (CBNs) have been utilized to develop nano- and microscale biosensors that enable real-time and continuous monitoring of biochemical and biophysical changes in living biological systems. The integration of CBN-based biosensors into organoids has recently provided valuable insights into organoid development, disease modeling, and drug responses, enhancing their functionality and expanding their applications in diverse biomedical fields. These biosensors have been particularly transformative in studying neurological disorders, cardiovascular diseases, cancer progression, and liver toxicity, where precise, non-invasive monitoring is crucial for understanding pathophysiological mechanisms and assessing therapeutic efficacy. This review introduces intra- and extracellular biosensors incorporating CBNs such as graphene, carbon nanotubes (CNTs), graphene oxide (GO), reduced graphene oxide (rGO), carbon dots (CDs), and fullerenes. Additionally, it discusses strategies for improving the biocompatibility of CBN-based biosensors and minimizing their potential toxicity to ensure long-term organoid viability. Key challenges such as biosensor integration, data accuracy, and functional compatibility with specific organoid models are also addressed. Furthermore, this review highlights how CBN-based biosensors enhance the precision and relevance of organoid models in biomedical research, particularly in organ-specific applications such as brain-on-a-chip systems for neurodegenerative disease studies, liver-on-a-chip platforms for hepatotoxicity screening, and cardiac organoids for assessing cardiotoxicity in drug development. Finally, it explores how biosensing technologies could revolutionize personalized medicine by enabling high throughput drug screening, patient-specific disease modeling, and integrated sensing platforms for early diagnostics. By capturing current advancements and future directions, this review underscores the transformative potential of carbon-based nanotechnology in organoid research and its broader impact on medical science.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"222 ","pages":"Article 115592"},"PeriodicalIF":15.2,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905717","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}
Elena Totter , Emilie von Einsiedel , Lisa Regazzoni, Simone Schuerle
{"title":"Paving the way for bacteria-based drug delivery: biohybrid microrobots emerging from microrobotics and synthetic biology","authors":"Elena Totter , Emilie von Einsiedel , Lisa Regazzoni, Simone Schuerle","doi":"10.1016/j.addr.2025.115577","DOIUrl":"10.1016/j.addr.2025.115577","url":null,"abstract":"<div><div>Advances in microrobotics and synthetic biology are paving the way for innovative solutions to long-standing challenges in drug delivery. Both fields have independently worked on engineering bacteria as a therapeutic system, focusing on enhancing propulsion, cargo delivery, detection, and biocompatibility. Bacteria, with their inherent adaptability and functional versatility, serve as an ideal foundation for these efforts, enabling them to navigate complex biological environments such as the human body.</div><div>This review explores the convergence of microrobotics and synthetic biology, which has catalysed the development of biohybrid bacterial microrobots that integrate the strengths of both disciplines. By incorporating external control modalities – such as light, ultrasound, and magnetic fields – these hybrid systems address the limitations of purely microrobotic or biological approaches, offering new opportunities to enhance precision and efficacy in targeted therapies.</div><div>However, realising the full potential of biohybrid bacterial microrobots requires overcoming critical challenges, such as ensuring compatibility between biological and synthetic components, scaling manufacturing processes, and defining regulatory pathways tailored to living therapeutics. Addressing these hurdles through joint, interdisciplinary research efforts, can unlock the transformative possibilities of these systems in modern medicine.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115577"},"PeriodicalIF":15.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841108","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}
Yujin Lee , Hyun Gi Koh , Kyoung Heon Kim , Yong-Su Jin , Bong Hyun Sung , Jungyeon Kim
{"title":"Enhancing the persistence of engineered biotherapeutics in the gut: Adhesion, glycan metabolism, and environmental resistance","authors":"Yujin Lee , Hyun Gi Koh , Kyoung Heon Kim , Yong-Su Jin , Bong Hyun Sung , Jungyeon Kim","doi":"10.1016/j.addr.2025.115591","DOIUrl":"10.1016/j.addr.2025.115591","url":null,"abstract":"<div><div>Engineered live biotherapeutic products (eLBPs) are receiving increasing attention as next-generation therapeutics to treat a variety of diseases with high specificity and effectiveness. Despite their potential, eLBPs face challenges, such as limited colonization, competition with native microbiota, nutrient depletion, and susceptibility to gastrointestinal stresses, which ultimately reduce their persistence in the gut and hinder their therapeutic efficacy. This review examines the key strategies to enhance the persistence and activity of eLBPs in the gut environment. First, methods to strengthen the adhesion capacity of eLBPs are discussed, including genetic engineering to express adhesins and chemical surface modifications to improve their binding to mucus and epithelial cells. Second, strategies to improve the ability of eLBPs to efficiently use mucin-derived sugars, which are continuously secreted by intestinal epithelial cells, were highlighted. These strategies involve the introduction and optimization of glycan-degrading enzymes and metabolic pathways for key mucin sugars, such as N-acetylglucosamine, galactose, and sialic acid, to support sustained energy production and enhance gut colonization. Third, strategies to improve the resistance of eLBPs against environmental stress are discussed, including genetic modifications to stabilize cell membranes, enhancement of ion pump activity, overexpression of stress-response proteins, and encapsulation techniques to provide protection. The implementation of these strategies can address challenges related to gut colonization by eLBPs, thereby enhancing their metabolic activity and enabling sustained and efficient secretion of therapeutic molecules. This review offers a comprehensive framework for developing and optimizing eLBPs, paving the way for their successful clinical application with enhanced effectiveness in treating gastrointestinal and systemic diseases.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115591"},"PeriodicalIF":15.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841109","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}