Pub Date : 2025-09-01Epub Date: 2025-07-09DOI: 10.1016/j.addr.2025.115650
Chinmayi R. Gudi , Michael J. Wannemuehler , Thomas J. Mansell
The gut-brain-immune (GBI) axis, connecting gut microbes, neural tissue, and the cells of the immune system, plays a critical role in human health, particularly in relation to neurological diseases. Research in this field over the last few decades shows that disruptions in the microbiome have been linked to chronic inflammation, which may contribute to neurological conditions, including Parkinson’s disease, Alzheimer’s disease, and other mental health disorders. As we gain a greater understanding of the links between these systems, novel therapeutic strategies are being explored to treat disease by modulation of the GBI axis. One of the most promising approaches is the use of live biotherapeutics, such as engineered probiotics, as next-generation drug delivery systems. These live microorganisms can be designed to deliver specific therapeutic compounds to the gut and brain in order to modulate immune responses and reduce inflammation at the source. Probiotics and live biotherapeutics can offer a targeted approach to treating neurological diseases by influencing both the microbiome and immune system. In this review, we outline the research and mechanisms that have been implicated in GBI interactions and highlight the potential of these innovative therapies in treating neurological disorders, emphasizing their role in improving precision medicine through targeted, microbiome-based interventions.
{"title":"Gut-brain-immune interactions: exploring probiotics as a drug delivery platform for neurological disease","authors":"Chinmayi R. Gudi , Michael J. Wannemuehler , Thomas J. Mansell","doi":"10.1016/j.addr.2025.115650","DOIUrl":"10.1016/j.addr.2025.115650","url":null,"abstract":"<div><div>The gut-brain-immune (GBI) axis, connecting gut microbes, neural tissue, and the cells of the immune system, plays a critical role in human health, particularly in relation to neurological diseases. Research in this field over the last few decades shows that disruptions in the microbiome have been linked to chronic inflammation, which may contribute to neurological conditions, including Parkinson’s disease, Alzheimer’s disease, and other mental health disorders. As we gain a greater understanding of the links between these systems, novel therapeutic strategies are being explored to treat disease by modulation of the GBI axis. One of the most promising approaches is the use of live biotherapeutics, such as engineered probiotics, as next-generation drug delivery systems. These live microorganisms can be designed to deliver specific therapeutic compounds to the gut and brain in order to modulate immune responses and reduce inflammation at the source. Probiotics and live biotherapeutics can offer a targeted approach to treating neurological diseases by influencing both the microbiome and immune system. In this review, we outline the research and mechanisms that have been implicated in GBI interactions and highlight the potential of these innovative therapies in treating neurological disorders, emphasizing their role in improving precision medicine through targeted, microbiome-based interventions.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115650"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594608","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}
Carbon dots (CDs), a class of carbonaceous and fluorescent nanomaterials with ultra-small dimensions (below 10 nm), have become popular nanoparticles in several fields, such as nanomedicine, catalysis, sensing or electronics. Due to their chemical versatility, luminescence, surface functional groups, biocompatibility and water solubility, they have been extensively studied in biomedical field. In this review, we focused on CDs used as nano contrast agents (nCAs) for fluorescence, magnetic resonance or computed tomography imaging in small animal models. We described the advantages of using CDs, highlighting some relevant examples, as well as the current issues that slow down their effective use in biomedicine, such as the rational synthetic design, scant purification and poor characterization. Lastly, we gathered some perspectives to develop carbon dots with more reliable properties and accomplish cutting-edge applications.
{"title":"Carbon dots as multi-modal contrast agents: opportunities and open challenges for in vivo bioimaging","authors":"Elisa Sturabotti , Beatriz Sierra-Serrano , Samantha Marcelino Apresto , Michele Cesco , Luca Comparini , Lucia Cardo , Maurizio Prato","doi":"10.1016/j.addr.2025.115659","DOIUrl":"10.1016/j.addr.2025.115659","url":null,"abstract":"<div><div>Carbon dots (CDs), a class of carbonaceous and fluorescent nanomaterials with ultra-small dimensions (below 10 nm), have become popular nanoparticles in several fields, such as nanomedicine, catalysis, sensing or electronics. Due to their chemical versatility, luminescence, surface functional groups, biocompatibility and water solubility, they have been extensively studied in biomedical field. In this review, we focused on CDs used as nano contrast agents (nCAs) for fluorescence, magnetic resonance or computed tomography imaging in small animal models. We described the advantages of using CDs, highlighting some relevant examples, as well as the current issues that slow down their effective use in biomedicine, such as the rational synthetic design, scant purification and poor characterization. Lastly, we gathered some perspectives to develop carbon dots with more reliable properties and accomplish cutting-edge applications.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115659"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684929","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}
Pub Date : 2025-09-01Epub Date: 2025-07-04DOI: 10.1016/j.addr.2025.115646
Ka-Ying Wong , Man-Sau Wong , Jung Heon Lee , Juewen Liu
Aptamers are nucleic acid-based ligands that can selectively bind to target molecules. Because of their unique target-binding properties, the use of aptamers for targeting cell surface molecules has attracted broad research interest. The field has evolved from selecting aptamers against purified surface proteins to using whole cells (cell-SELEX) as targets. To further advance the field, the concept of tissue-SELEX was later proposed to ensure that selected aptamers possess optimal binding properties in more native in vivo environments. In this article, we review recent progress made for tissue-SELEX, covering methods including tissue slide-based SELEX, morph-X-SELEX, ex vivo-SELEX, and microfluidic tissue-SELEX. The target tissues include cornea, breast, ovary, lung, cardiac and thyroid tissues. For the diseases targeted, cancer is the most extensively studied followed by cardiomyopathies and vascular conditions. The advantages of each method are discussed and potential limitations are also critically reviewed. Applications of tissue- or in vivo-SELEX-derived aptamers in drug delivery include local administration for ocular diseases and systemic administration for lung cancer. Finally, future directions are discussed, emphasizing the need for systematic comparative studies to evaluate cell-SELEX and tissue-SELEX derived aptamers, using antibodies as benchmarks to guide the development of clinically relevant therapeutic applications.
{"title":"From cell-SELEX to tissue-SELEX for targeted drug delivery and aptamer nanomedicine","authors":"Ka-Ying Wong , Man-Sau Wong , Jung Heon Lee , Juewen Liu","doi":"10.1016/j.addr.2025.115646","DOIUrl":"10.1016/j.addr.2025.115646","url":null,"abstract":"<div><div>Aptamers are nucleic acid-based ligands that can selectively bind to target molecules. Because of their unique target-binding properties, the use of aptamers for targeting cell surface molecules has attracted broad research interest. The field has evolved from selecting aptamers against purified surface proteins to using whole cells (cell-SELEX) as targets. To further advance the field, the concept of tissue-SELEX was later proposed to ensure that selected aptamers possess optimal binding properties in more native <em>in vivo</em> environments. In this article, we review recent progress made for tissue-SELEX, covering methods including tissue slide-based SELEX, morph-X-SELEX, <em>ex vivo</em>-SELEX, and microfluidic tissue-SELEX. The target tissues include cornea, breast, ovary, lung, cardiac and thyroid tissues. For the diseases targeted, cancer is the most extensively studied followed by cardiomyopathies and vascular conditions. The advantages of each method are discussed and potential limitations are also critically reviewed. Applications of tissue- or <em>in vivo</em>-SELEX-derived aptamers in drug delivery include local administration for ocular diseases and systemic administration for lung cancer. Finally, future directions are discussed, emphasizing the need for systematic comparative studies to evaluate cell-SELEX and tissue-SELEX derived aptamers, using antibodies as benchmarks to guide the development of clinically relevant therapeutic applications.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115646"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565822","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}
Pub Date : 2025-09-01Epub Date: 2025-07-30DOI: 10.1016/j.addr.2025.115660
Dandan Li , Huarui Liu , Xintong Li , Changping Yang , Hanyin Zhu , Hong Wang , Jianbing Liu , Baoquan Ding
DNA, as a carrier of genetic information, has further been efficiently utilized as a foundational element in creating diverse nanostructures of different shapes and sizes through precise base pairing. With spatial addressability, structural programmability, and remarkable biocompatibility, self-assembled DNA-based nanostructures have been broadly applied in various biomedical research areas, such as bio-imaging, disease diagnosis, and drug delivery. Of particular note, immunotherapy, known for its outstanding therapeutic efficacy, has garnered much attention. In this review, we highlight the recent applications of DNA-based nanostructures (including DNA junction, DNA polyhedron, DNA origami, RCA-based DNA structure, DNA hydrogel, and spherical nucleic acid) in immunotherapy (based on the delivery of CpG adjuvant, tumor antigen, PD1 inhibitor, mRNA vaccine, virus antigen, or direct regulating immune cells). Furthermore, the challenges and future prospects of DNA-based nanostructures for in vivo immunotherapy are discussed.
{"title":"Applications of DNA-based nanostructures in immunotherapy","authors":"Dandan Li , Huarui Liu , Xintong Li , Changping Yang , Hanyin Zhu , Hong Wang , Jianbing Liu , Baoquan Ding","doi":"10.1016/j.addr.2025.115660","DOIUrl":"10.1016/j.addr.2025.115660","url":null,"abstract":"<div><div>DNA, as a carrier of genetic information, has further been efficiently utilized as a foundational element in creating diverse nanostructures of different shapes and sizes through precise base pairing. With spatial addressability, structural programmability, and remarkable biocompatibility, self-assembled DNA-based nanostructures have been broadly applied in various biomedical research areas, such as bio-imaging, disease diagnosis, and drug delivery. Of particular note, immunotherapy, known for its outstanding therapeutic efficacy, has garnered much attention. In this review, we highlight the recent applications of DNA-based nanostructures (including DNA junction, DNA polyhedron, DNA origami, RCA-based DNA structure, DNA hydrogel, and spherical nucleic acid) in immunotherapy (based on the delivery of CpG adjuvant, tumor antigen, PD1 inhibitor, mRNA vaccine, virus antigen, or direct regulating immune cells). Furthermore, the challenges and future prospects of DNA-based nanostructures for <em>in vivo</em> immunotherapy are discussed.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115660"},"PeriodicalIF":17.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737742","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}
Pub Date : 2025-09-01Epub Date: 2025-07-17DOI: 10.1016/j.addr.2025.115655
Mrutyunjaya Panda , Maria Fakitsa , Maria Markaki , Nektarios Tavernarakis
An increase in the aging population is accompanied by increased susceptibility to age-associated neurodegeneration, with currently no cure. Despite the diversity of symptoms and etiologies, neurodegenerative disorders share mechanistic commonalities and many pathophysiological features. These include disruptions in circadian rhythms that affect neuronal physiology. Systematic investigations in several animal models have advanced our understanding of the molecular processes that link circadian rhythms and neurodegenerative disease states. These models have also been used to screen and validate promising chronotherapeutic drug candidates that target the circadian clock to ameliorate neurodegeneration. With the emergence of robust and reliable methodologies to measure daily rhythms, the nematode model Caenorhabditis elegans has become a versatile tool for high throughput chronotherapeutic drug screening against neurodegenerative disorders. In this review, we discuss the unique features and advantages of C. elegans as an enabling platform for chronotherapeutic drug discovery, towards the development of innovative strategies for the treatment of human neurodegenerative conditions.
{"title":"Caenorhabditis elegans as an emerging high throughput chronotherapeutic drug screening platform for human neurodegenerative disorders","authors":"Mrutyunjaya Panda , Maria Fakitsa , Maria Markaki , Nektarios Tavernarakis","doi":"10.1016/j.addr.2025.115655","DOIUrl":"10.1016/j.addr.2025.115655","url":null,"abstract":"<div><div>An increase in the aging population is accompanied by increased susceptibility to age-associated neurodegeneration, with currently no cure. Despite the diversity of symptoms and etiologies, neurodegenerative disorders share mechanistic commonalities and many pathophysiological features. These include disruptions in circadian rhythms that affect neuronal physiology. Systematic investigations in several animal models have advanced our understanding of the molecular processes that link circadian rhythms and neurodegenerative disease states. These models have also been used to screen and validate promising chronotherapeutic drug candidates that target the circadian clock to ameliorate neurodegeneration. With the emergence of robust and reliable methodologies to measure daily rhythms, the nematode model <em>Caenorhabditis elegans</em> has become a versatile tool for high throughput chronotherapeutic drug screening against neurodegenerative disorders. In this review, we discuss the unique features and advantages of <em>C. elegans</em> as an enabling platform for chronotherapeutic drug discovery, towards the development of innovative strategies for the treatment of human neurodegenerative conditions.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115655"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645548","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}
Pub Date : 2025-09-01Epub Date: 2025-07-17DOI: 10.1016/j.addr.2025.115656
Konstantinos Loukelis , Udayabhanu Jammalamadaka , Antonios G. Mikos
Over the years, sustained research into the role of biomolecules in bone regeneration has provided valuable insights into their potential as therapeutic agents for tissue growth. However, challenges such as short half-lives and high production costs underscore the need for advanced tissue engineering platforms. Precise spatial delivery of these biomolecules to target sites remains a critical requirement. 3D printing has emerged as a powerful technology, enabling the layer-by-layer fabrication of hierarchically complex 3D structures with tailored biomechanical properties. Additionally, it facilitates the preservation and delivery of bioactive molecules following desirable kinetic patterns. This review highlights the most recent and notable advancements of 3D printing-enabled spatial patterning of biological cues aimed at promoting the formation of bone tissue, vascularized bone, osteochondral tissue, and bone-tendon interface.
{"title":"3D printing-enabled spatial patterning of biomimetic signals for bone tissue engineering","authors":"Konstantinos Loukelis , Udayabhanu Jammalamadaka , Antonios G. Mikos","doi":"10.1016/j.addr.2025.115656","DOIUrl":"10.1016/j.addr.2025.115656","url":null,"abstract":"<div><div>Over the years, sustained research into the role of biomolecules in bone regeneration has provided valuable insights into their potential as therapeutic agents for tissue growth. However, challenges such as short half-lives and high production costs underscore the need for advanced tissue engineering platforms. Precise spatial delivery of these biomolecules to target sites remains a critical requirement. 3D printing has emerged as a powerful technology, enabling the layer-by-layer fabrication of hierarchically complex 3D structures with tailored biomechanical properties. Additionally, it facilitates the preservation and delivery of bioactive molecules following desirable kinetic patterns. This review highlights the most recent and notable advancements of 3D printing-enabled spatial patterning of biological cues aimed at promoting the formation of bone tissue, vascularized bone, osteochondral tissue, and bone-tendon interface.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115656"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652217","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}
Pub Date : 2025-09-01Epub Date: 2025-06-27DOI: 10.1016/j.addr.2025.115642
Johann Gout , Menar Ekizce , Elodie Roger , Alexander Kleger
Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid malignancy, rapidly progressing and highly therapeutic resistant, as reflected by its very low five-year overall survival. Despite significant advancements in our understanding of its pathobiology and the molecular mechanisms driving its tumorigenesis, therapeutic options remain limited and yield only modest clinical responses. PDAC is characterized by a high genetic inter and intratumoral heterogeneity that shapes its mutational landscape and affects its response to therapies. Facing the limitations of existing preclinical models, the development of personalized medicine in PDAC has been hampered. Translational pancreatic cancer research has been accelerated by the emergence of patient-derived organoids (PDOs), in vitro models faithfully preserving genetic, transcriptomic, proteomic, and epigenetic features and heterogeneity of the parental tumors. This review presents how PDO models can revolutionize precision oncology in pancreatic cancer by prognosticating tumor response and thereby, assist clinical decision-making. Their potential as a preclinical platform for biomarker and drug discovery, as well as future directions for enhancing the therapy response predictive power of organoid-based systems are also discussed.
{"title":"Pancreatic organoids as cancer avatars for true personalized medicine","authors":"Johann Gout , Menar Ekizce , Elodie Roger , Alexander Kleger","doi":"10.1016/j.addr.2025.115642","DOIUrl":"10.1016/j.addr.2025.115642","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid malignancy, rapidly progressing and highly therapeutic resistant, as reflected by its very low five-year overall survival. Despite significant advancements in our understanding of its pathobiology and the molecular mechanisms driving its tumorigenesis, therapeutic options remain limited and yield only modest clinical responses. PDAC is characterized by a high genetic inter and intratumoral heterogeneity that shapes its mutational landscape and affects its response to therapies. Facing the limitations of existing preclinical models, the development of personalized medicine in PDAC has been hampered. Translational pancreatic cancer research has been accelerated by the emergence of patient-derived organoids (PDOs), <em>in vitro</em> models faithfully preserving genetic, transcriptomic, proteomic, and epigenetic features and heterogeneity of the parental tumors. This review presents how PDO models can revolutionize precision oncology in pancreatic cancer by prognosticating tumor response and thereby, assist clinical decision-making. Their potential as a preclinical platform for biomarker and drug discovery, as well as future directions for enhancing the therapy response predictive power of organoid-based systems are also discussed.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115642"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503923","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}
Drug delivery is a process to deliver the required amount of a drug to a target site within an appropriate timeframe, while minimizing possible side effects and maximizing efficiency. This is accomplished by drug delivery systems (DDSs), which are platforms composed of natural and/or synthetic materials that carry drugs or bioactive agents at a particular site or throughout a patient's body via oral, transdermal, topical, intravenous, or intramuscular routes to minimize the drug’s toxicity and provide desired therapeutic effects without affecting the patient’s healthy cells, tissues or organs. Despite significant advancements, drug delivery still faces numerous scientific, technological, and clinical challenges, such as poor drug bioavailability, unstable loading efficiency, lack of site-specificity, undesired prolonged delivery of drugs. Issues such as drug stability, limitations in achieving controlled and sustained release, long-term unwanted toxicity, and patient compliance are also common challenges in the field. In recent years, researchers have created 'Metamaterials', which exploit the advancements in fabrication and 3D printing technology to exhibit complex characteristics and customizable architecture that are not otherwise naturally present in a material. These properties provide a precision control over drug release kinetics, targeting, and efficiency by precise manipulation of interactions at the nanoscale. This review explores the potential of metamaterials in developing advanced DDSs with exceptional precision and efficacy, via materials selection, design considerations, fabrication challenges, and optimization strategies for 3D printing of these materials. We provide an overview of their recent application in drug delivery tackling the challenges associated with release systems, including sustained, pulsatile, and on-demand delivery modalities. Targeted delivery, theranostic applications, and regenerative medicine, are also explored. We believe this review will inspire further research and development in this burgeoning field by highlighting the challenges associated with their biocompatibility, scalability, manufacturing considerations, and hurdles or opportunities in translation, ultimately leading to transformative advancements in personalized medicine and healthcare.
{"title":"3D printed metamaterials: properties, fabrication, and drug delivery applications","authors":"Hemant Singh , Muath Tuffaha , Shivi Tripathi , Ayça Bal Öztürk , Harshil Dave , Mukesh Dhanka , Huseyin Avci , Himansu Sekhar Nanda , Shabir Hassan","doi":"10.1016/j.addr.2025.115636","DOIUrl":"10.1016/j.addr.2025.115636","url":null,"abstract":"<div><div>Drug delivery is a process to deliver the required amount of a drug to a target site within an appropriate timeframe, while minimizing possible side effects and maximizing efficiency. This is accomplished by drug delivery systems (DDSs), which are platforms composed of natural and/or synthetic materials that carry drugs or bioactive agents at a particular site or throughout a patient's body via oral, transdermal, topical, intravenous, or intramuscular routes to minimize the drug’s toxicity and provide desired therapeutic effects without affecting the patient’s healthy cells, tissues or organs. Despite significant advancements, drug delivery still faces numerous scientific, technological, and clinical challenges, such as poor drug bioavailability, unstable loading efficiency, lack of site-specificity, undesired prolonged delivery of drugs. Issues such as drug stability, limitations in achieving controlled and sustained release, long-term unwanted toxicity, and patient compliance are also common challenges in the field. In recent years, researchers have created 'Metamaterials', which exploit the advancements in fabrication and 3D printing technology to exhibit complex characteristics and customizable architecture that are not otherwise naturally present in a material. These properties provide a precision control over drug release kinetics, targeting, and efficiency by precise manipulation of interactions at the nanoscale. This review explores the potential of metamaterials in developing advanced DDSs with exceptional precision and efficacy, via materials selection, design considerations, fabrication challenges, and optimization strategies for 3D printing of these materials. We provide an overview of their recent application in drug delivery tackling the challenges associated with release systems, including sustained, pulsatile, and on-demand delivery modalities. Targeted delivery, theranostic applications, and regenerative medicine, are also explored. We believe this review will inspire further research and development in this burgeoning field by highlighting the challenges associated with their biocompatibility, scalability, manufacturing considerations, and hurdles or opportunities in translation, ultimately leading to transformative advancements in personalized medicine and healthcare.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115636"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252534","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}
Pub Date : 2025-09-01Epub Date: 2025-06-14DOI: 10.1016/j.addr.2025.115637
Giulia Porro , Marco Basile , Zhengdong Xie , Gian Marco Tuveri , Giuseppe Battaglia , Cátia D.F. Lopes
Efficient drug delivery across the blood–brain barrier (BBB) remains a significant obstacle in treating central nervous system (CNS) disorders. This review provides an in-depth analysis of the structural and molecular mechanisms underlying BBB integrity and its functional properties. We detail the role of key cellular and molecular components that regulate selective molecular transport across the barrier, alongside a description of the current therapeutic approaches for brain drug delivery, including those leveraging receptor-mediated transcytosis. Emphasis is placed on multivalency-based strategies that enhance the specificity of nanoparticle targeting and improve transport efficacy across the BBB. Additionally, we discuss the added value of integrating mathematical and computational models with experimental validation for accelerating BBB-targeted delivery systems optimisation.
{"title":"A new era in brain drug delivery: Integrating multivalency and computational optimisation for blood–brain barrier permeation","authors":"Giulia Porro , Marco Basile , Zhengdong Xie , Gian Marco Tuveri , Giuseppe Battaglia , Cátia D.F. Lopes","doi":"10.1016/j.addr.2025.115637","DOIUrl":"10.1016/j.addr.2025.115637","url":null,"abstract":"<div><div>Efficient drug delivery across the blood–brain barrier (BBB) remains a significant obstacle in treating central nervous system (CNS) disorders. This review provides an in-depth analysis of the structural and molecular mechanisms underlying BBB integrity and its functional properties. We detail the role of key cellular and molecular components that regulate selective molecular transport across the barrier, alongside a description of the current therapeutic approaches for brain drug delivery, including those leveraging receptor-mediated transcytosis. Emphasis is placed on multivalency-based strategies that enhance the specificity of nanoparticle targeting and improve transport efficacy across the BBB. Additionally, we discuss the added value of integrating mathematical and computational models with experimental validation for accelerating BBB-targeted delivery systems optimisation.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115637"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288633","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}
Pub Date : 2025-09-01Epub Date: 2025-06-11DOI: 10.1016/j.addr.2025.115639
Gabriele Coppola , Fabiola Cennamo , Giuseppe Ciccone , Maria Luigia Ibba , Annalisa Di Ruscio , Aldo Di Vito , Carla Lucia Esposito , Silvia Catuogno
The possibility of correcting genetic and epigenetic alterations through gene therapies has been considered a cornerstone in oncology. However, modest results have been achieved in clinics, mainly due to inefficient tumor targeting and side effects. Nucleic acid aptamers are three-dimensional folded single-stranded DNAs or RNAs that selectively bind receptors on cellular membranes, being subsequently internalized via receptor-mediated endocytosis. Thanks to this capability, internalizing aptamers have been investigated as targeting moieties to deliver gene therapies more efficiently and selectively in tumor cells. Promising preclinical results suggested that aptamers could represent the long-awaited step forward in cancer gene therapy. Nevertheless, no clinical trials of aptamer-based gene therapies have been carried out two decades after the first preclinical application, indicating the field could not be sufficiently mature for translatability.
The review aims to update the state of the art regarding aptamers’ contribution to gene therapy delivery and to critically highlight the main shortcomings that could have hindered clinical evaluations. In addition, pioneering insights regarding the use of aptamers as co-factors in CRISPR/Cas9 technology or as direct epigenetic regulators are also summarized, revealing more extended applicability not limited to the delivery of cancer gene therapies.
{"title":"Aptamer-based applications in delivering cancer gene therapies and beyond: state of the art and the missing links to clinical translation","authors":"Gabriele Coppola , Fabiola Cennamo , Giuseppe Ciccone , Maria Luigia Ibba , Annalisa Di Ruscio , Aldo Di Vito , Carla Lucia Esposito , Silvia Catuogno","doi":"10.1016/j.addr.2025.115639","DOIUrl":"10.1016/j.addr.2025.115639","url":null,"abstract":"<div><div>The possibility of correcting genetic and epigenetic alterations through gene therapies has been considered a cornerstone in oncology. However, modest results have been achieved in clinics, mainly due to inefficient tumor targeting and side effects. Nucleic acid aptamers are three-dimensional folded single-stranded DNAs or RNAs that selectively bind receptors on cellular membranes, being subsequently internalized via receptor-mediated endocytosis. Thanks to this capability, internalizing aptamers have been investigated as targeting moieties to deliver gene therapies more efficiently and selectively in tumor cells. Promising preclinical results suggested that aptamers could represent the long-awaited step forward in cancer gene therapy. Nevertheless, no clinical trials of aptamer-based gene therapies have been carried out two decades after the first preclinical application, indicating the field could not be sufficiently mature for translatability.</div><div>The review aims to update the<!--> <!-->state of the art regarding aptamers’ contribution to gene therapy delivery and to critically highlight the main shortcomings that could have hindered clinical evaluations. In addition, pioneering insights regarding the use of aptamers as co-factors in CRISPR/Cas9 technology or as direct epigenetic regulators are also summarized, revealing more extended applicability not limited to the delivery of cancer gene therapies.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"224 ","pages":"Article 115639"},"PeriodicalIF":15.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269250","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}
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