Pub Date : 2025-04-16DOI: 10.1016/j.addr.2025.115577
Elena Totter, Emilie von Einsiedel, Lisa Regazzoni, Simone Schuerle
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.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.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.
{"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":"https://doi.org/10.1016/j.addr.2025.115577","url":null,"abstract":"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.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.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.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"3 1","pages":""},"PeriodicalIF":16.1,"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}
Pub Date : 2025-04-16DOI: 10.1016/j.addr.2025.115591
Yujin Lee , Hyun Gi Koh , Kyoung Heon Kim , Yong-Su Jin , Bong Hyun Sung , Jungyeon Kim
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.
{"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}
Pub Date : 2025-04-15DOI: 10.1016/j.addr.2025.115590
Jiahua Zhang , Linjie Ma , Yong Hou , Haoyi Ouyang , Hyunsik Hong , Kanghyeon Kim , Heemin Kang , Zhiqin Chu
Cells constantly produce elusive bio-signals, such as cellular forces, free radicals, and molecular interactions, that are important for understanding diseases and treatment effects. However, detecting these signals is challenging because of issues with sensitivity, specificity, and the complexity of biological systems. Owing to their unique properties, nanodiamonds have emerged as a promising platform for detecting such elusive bio-signals, providing enhanced precision and effectiveness in diagnostics and therapies. In this review, we explore the detection of intracellular elusive bio-signals using nitrogen-vacancy (NV) centers in nanodiamonds, presenting case studies on their applications in cell force, free radicals, molecular interactions, and nanoscale thermometry. Moreover, we explore the design and applications of nanodiamonds as nanocarriers in quantum sensors and drug delivery systems.
{"title":"Nanodiamond-Based Sensing: A revolution for biosensors in capturing elusive bio-signals in living cells","authors":"Jiahua Zhang , Linjie Ma , Yong Hou , Haoyi Ouyang , Hyunsik Hong , Kanghyeon Kim , Heemin Kang , Zhiqin Chu","doi":"10.1016/j.addr.2025.115590","DOIUrl":"10.1016/j.addr.2025.115590","url":null,"abstract":"<div><div>Cells constantly produce elusive bio-signals, such as cellular forces, free radicals, and molecular interactions, that are important for understanding diseases and treatment effects. However, detecting these signals is challenging because of issues with sensitivity, specificity, and the complexity of biological systems. Owing to their unique properties, nanodiamonds have emerged as a promising platform for detecting such elusive bio-signals, providing enhanced precision and effectiveness in diagnostics and therapies. In this review, we explore the detection of intracellular elusive bio-signals using nitrogen-vacancy (NV) centers in nanodiamonds, presenting case studies on their applications in cell force, free radicals, molecular interactions, and nanoscale thermometry. Moreover, we explore the design and applications of nanodiamonds as nanocarriers in quantum sensors and drug delivery systems.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115590"},"PeriodicalIF":15.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837503","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 : 2025-04-12DOI: 10.1016/j.addr.2025.115579
Jaehyun Lee , Sandra McClure , Ralph R. Weichselbaum , Mark Mimee
Humans are home to a diverse community of bacteria, many of which form symbiotic relationships with their host. Notably, tumors can also harbor their own unique bacterial populations that can influence tumor growth and progression. These bacteria, which selectively colonize hypoxic and acidic tumor microenvironments, present a novel therapeutic strategy to combat cancer. Advancements in synthetic biology enable us to safely and efficiently program therapeutic drug production in bacteria, further enhancing their potential. This review provides a comprehensive guide to utilizing bacteria for cancer treatment. We discuss key considerations for selecting bacterial strains, emphasizing their colonization efficiency, the delicate balance between safety and anti-tumor efficacy, and the availability of tools for genetic engineering. We also delve into strategies for precise spatiotemporal control of drug delivery to minimize adverse effects and maximize therapeutic impact, exploring recent examples of engineered bacteria designed to combat tumors. Finally, we address the underlying challenges and future prospects of bacterial cancer therapy. This review underscores the versatility of bacterial therapies and outlines strategies to fully harness their potential in the fight against cancer.
{"title":"Designing live bacterial therapeutics for cancer","authors":"Jaehyun Lee , Sandra McClure , Ralph R. Weichselbaum , Mark Mimee","doi":"10.1016/j.addr.2025.115579","DOIUrl":"10.1016/j.addr.2025.115579","url":null,"abstract":"<div><div>Humans are home to a diverse community of bacteria, many of which form symbiotic relationships with their host. Notably, tumors can also harbor their own unique bacterial populations that can influence tumor growth and progression. These bacteria, which selectively colonize hypoxic and acidic tumor microenvironments, present a novel therapeutic strategy to combat cancer. Advancements in synthetic biology enable us to safely and efficiently program therapeutic drug production in bacteria, further enhancing their potential. This review provides a comprehensive guide to utilizing bacteria for cancer treatment. We discuss key considerations for selecting bacterial strains, emphasizing their colonization efficiency, the delicate balance between safety and anti-tumor efficacy, and the availability of tools for genetic engineering. We also delve into strategies for precise spatiotemporal control of drug delivery to minimize adverse effects and maximize therapeutic impact, exploring recent examples of engineered bacteria designed to combat tumors. Finally, we address the underlying challenges and future prospects of bacterial cancer therapy. This review underscores the versatility of bacterial therapies and outlines strategies to fully harness their potential in the fight against cancer.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115579"},"PeriodicalIF":15.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822648","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 : 2025-04-12DOI: 10.1016/j.addr.2025.115587
Atsuta Ozaki , Daiki Sakai , Michiko Mandai
Degenerative retinal diseases, such as age-related macular degeneration (AMD) and inherited retinal diseases (IRDs), cause visual impairment due to irreversible damage to the retinal pigment epithelium (RPE) and photoreceptor cells (PRCs). Currently, no definitive treatment exists. However, cell-based therapies using induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) offer potential solutions for restoring damaged retinal cells. This review summarizes recent advances in RPE and PRC transplantation, highlighting the benefits of each approach. For RPE transplantation, we focus on the outcomes of clinical studies involving three formulations: RPE sheets, RPE suspensions, and RPE strips. In the context of PRC transplantation, we trace the progress from fetal retinal transplantation to the latest studies. Additionally, we discuss our recent clinical work with retinal sheet transplantation and genome-edited retinal organoid sheets, which aim to improve functional integration by reducing bipolar cells in grafts. Finally, with the overall safety of the regenerative cell-based therapies demonstrated in past clinical applications, we explore future prospects for these therapies.
{"title":"hPSC-based treatment of retinal diseases – Current progress and challenges","authors":"Atsuta Ozaki , Daiki Sakai , Michiko Mandai","doi":"10.1016/j.addr.2025.115587","DOIUrl":"10.1016/j.addr.2025.115587","url":null,"abstract":"<div><div>Degenerative retinal diseases, such as age-related macular degeneration (AMD) and inherited retinal diseases (IRDs), cause visual impairment due to irreversible damage to the retinal pigment epithelium (RPE) and photoreceptor cells (PRCs). Currently, no definitive treatment exists. However, cell-based therapies using induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) offer potential solutions for restoring damaged retinal cells. This review summarizes recent advances in RPE and PRC transplantation, highlighting the benefits of each approach. For RPE transplantation, we focus on the outcomes of clinical studies involving three formulations: RPE sheets, RPE suspensions, and RPE strips. In the context of PRC transplantation, we trace the progress from fetal retinal transplantation to the latest studies. Additionally, we discuss our recent clinical work with retinal sheet transplantation and genome-edited retinal organoid sheets, which aim to improve functional integration by reducing bipolar cells in grafts. Finally, with the overall safety of the regenerative cell-based therapies demonstrated in past clinical applications, we explore future prospects for these therapies.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115587"},"PeriodicalIF":15.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822598","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 : 2025-04-11DOI: 10.1016/j.addr.2025.115578
Tae Seok Moon
Technological advances in engineering biology or synthetic biology have enabled practical applications of genetically engineered microbes (GEMs), including their use as living diagnostics and vehicles for therapeutics. However, technological and non-technological issues associated with biocontainment of GEMs have yet to be addressed before fully realizing their potential. In this short perspective, I briefly discuss the relevant technologies for GEM biocontainment as well as environmental impacts, regulatory issues, and public perception of GEMs.
{"title":"Be a GEM: Biocontained, environmentally applied, genetically engineered microbes","authors":"Tae Seok Moon","doi":"10.1016/j.addr.2025.115578","DOIUrl":"10.1016/j.addr.2025.115578","url":null,"abstract":"<div><div>Technological advances in engineering biology or synthetic biology have enabled practical applications of genetically engineered microbes (GEMs), including their use as living diagnostics and vehicles for therapeutics. However, technological and non-technological issues associated with biocontainment of GEMs have yet to be addressed before fully realizing their potential. In this short perspective, I briefly discuss the relevant technologies for GEM biocontainment as well as environmental impacts, regulatory issues, and public perception of GEMs.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115578"},"PeriodicalIF":15.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822658","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 : 2025-04-03DOI: 10.1016/j.addr.2025.115576
Sepideh Khoshnevis, Michael H. Smolensky, Shahab Haghayegh
This review focuses on (i) 24 h patterns in the symptom intensity of common neurologic and psychiatric disorders and (ii) medications prescribed for their management that have a recommended administration time or schedule, presumably to potentiate desired and minimize undesired effects and by definition qualify them as chronotherapies. Predictable-in-time patterning of symptoms is exhibited by many neurologic − headaches, multiple sclerosis, neurogenic orthostatic hypotension, neuropathic pain, Parkinson’s disease, epileptic seizure, attention deficit hyperactivity, Alzheimer’s disease − and psychiatric − eating, depressive, obsessive–compulsive, post-traumatic stress, anxiety, and panic − disorders, due either to circadian rhythms of disease pathophysiology or inadequacies of medication-delivery systems. Circadian disruption and circadian misalignment of the sleep-wake and other 24 h rhythms plus late chronotype are characteristic of many of these disorders, suggesting involvement in the mechanisms or consequence of their pathology or as an adverse effect of therapy, especially when administered at an inappropriate biological time. The Prescribers’ Digital Reference, a compendium of all prescription medications approved for marketing in the US, reveals 65 of them are utilized to manage neurologic and psychiatric disorders by a recommended specified time-of-day or an asymmetrical interval or strength of dose schedule, presumably to optimize beneficial and minimize adverse effects, thereby qualifying them as chronotherapies. Overall, the contents of this review are intended to inform the development of future chronotherapies that incorporate state-of-the-art drug-delivery systems to improve management of neurologic and psychiatric disorders and associated circadian malalignment and disruption.
{"title":"Circadian attributes of neurological and psychiatric disorders as basis for their medication chronotherapy","authors":"Sepideh Khoshnevis, Michael H. Smolensky, Shahab Haghayegh","doi":"10.1016/j.addr.2025.115576","DOIUrl":"https://doi.org/10.1016/j.addr.2025.115576","url":null,"abstract":"This review focuses on (i) 24 h patterns in the symptom intensity of common neurologic and psychiatric disorders and (ii) medications prescribed for their management that have a recommended administration time or schedule, presumably to potentiate desired and minimize undesired effects and by definition qualify them as chronotherapies. Predictable-in-time patterning of symptoms is exhibited by many neurologic − headaches, multiple sclerosis, neurogenic orthostatic hypotension, neuropathic pain, Parkinson’s disease, epileptic seizure, attention deficit hyperactivity, Alzheimer’s disease − and psychiatric − eating, depressive, obsessive–compulsive, post-traumatic stress, anxiety, and panic − disorders, due either to circadian rhythms of disease pathophysiology or inadequacies of medication-delivery systems. Circadian disruption and circadian misalignment of the sleep-wake and other 24 h rhythms plus late chronotype are characteristic of many of these disorders, suggesting involvement in the mechanisms or consequence of their pathology or as an adverse effect of therapy, especially when administered at an inappropriate biological time. The Prescribers’ Digital Reference, a compendium of all prescription medications approved for marketing in the US, reveals 65 of them are utilized to manage neurologic and psychiatric disorders by a recommended specified time-of-day or an asymmetrical interval or strength of dose schedule, presumably to optimize beneficial and minimize adverse effects, thereby qualifying them as chronotherapies. Overall, the contents of this review are intended to inform the development of future chronotherapies that incorporate state-of-the-art drug-delivery systems to improve management of neurologic and psychiatric disorders and associated circadian malalignment and disruption.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"73 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776029","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 : 2025-04-03DOI: 10.1016/j.addr.2025.115574
Seung Ho Lee , Roemer Pott Hofstede , Adrián Noriega de la Colina , John H. Gunton , Joshua D. Bernstock , Giovanni Traverso
Implantable systems for neurological chronotherapy are poised to revolutionize the treatment of central nervous system diseases and disorders. These devices enable precise, time-controlled drug delivery aligned with the body’s circadian rhythms, optimizing therapeutic outcomes. By bypassing the blood–brain barrier, they achieve high local drug concentrations while minimizing systemic side effects, offering significant advantages for conditions where traditional therapies often fall short.
Platforms like SynchroMed II and CraniUS showcase this innovation, providing programmable delivery for conditions such as epilepsy and glioblastoma, with customizable profiles ranging from continuous infusion to timed bolus administration. Preclinical and clinical studies underscore the efficacy of aligning drug delivery with circadian rhythms, enhancing outcomes in chrono-chemotherapy and anti-epileptic treatments.
Despite their promise, challenges remain, including the invasiveness of implantation within the brain, device longevity, synchronization complexities, and cost(s). Accordingly, this review explores the current state of implantable neurological systems that may be leveraged for chronotherapy, their applications, limitations, and potential to transform neurological disease/disorder management.
{"title":"Implantable systems for neurological chronotherapy","authors":"Seung Ho Lee , Roemer Pott Hofstede , Adrián Noriega de la Colina , John H. Gunton , Joshua D. Bernstock , Giovanni Traverso","doi":"10.1016/j.addr.2025.115574","DOIUrl":"10.1016/j.addr.2025.115574","url":null,"abstract":"<div><div>Implantable systems for neurological chronotherapy are poised to revolutionize the treatment of central nervous system diseases and disorders. These devices enable precise, time-controlled drug delivery aligned with the body’s circadian rhythms, optimizing therapeutic outcomes. By bypassing the blood–brain barrier, they achieve high local drug concentrations while minimizing systemic side effects, offering significant advantages for conditions where traditional therapies often fall short.</div><div>Platforms like SynchroMed II and CraniUS showcase this innovation, providing programmable delivery for conditions such as epilepsy and glioblastoma, with customizable profiles ranging from continuous infusion to timed bolus administration. Preclinical and clinical studies underscore the efficacy of aligning drug delivery with circadian rhythms, enhancing outcomes in chrono-chemotherapy and anti-epileptic treatments.</div><div>Despite their promise, challenges remain, including the invasiveness of implantation within the brain, device longevity, synchronization complexities, and cost(s). Accordingly, this review explores the current state of implantable neurological systems that may be leveraged for chronotherapy, their applications, limitations, and potential to transform neurological disease/disorder management.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"221 ","pages":"Article 115574"},"PeriodicalIF":15.2,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766381","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 : 2025-04-02DOI: 10.1016/j.addr.2025.115573
Artur Galushkin, Illana Gozes
In this review we examine the neuroprotective potential of NAP (davunetide), a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP), in the context of neurodevelopmental and neurodegenerative disorders. ADNP, a protein essential for brain development and function, is associated with tauopathy-related diseases, such as Alzheimer’s Disease (AD), and circadian rhythm regulation. NAP enhances microtubule stability and prevents tauopathy. In preclinical studies, NAP shows promise in improving cognitive performance and correcting behavioral deficits in different models. Clinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated its safety, favorable bioavailability, and potential efficacy in improving cognitive function, making it a viable therapeutic option. In the pure tauopathy, progressive supranuclear palsy, NAP (davunetide) significantly slowed disease progression in women in a phase II-III clinical trial. Additionally, the complex interactions between ADNP, associated pathways, and circadian regulation and the extensive NAP compensation upon ADNP deficiency attest to further clinical development. Thus, NAP is an example of a reductionist approach in drug delivery, replacing/enhancing the critical large ADNP-related pathways including dysregulated microtubules and tauopathy with a small brain bioavailable investigational drug, davunetide.
{"title":"Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity","authors":"Artur Galushkin, Illana Gozes","doi":"10.1016/j.addr.2025.115573","DOIUrl":"10.1016/j.addr.2025.115573","url":null,"abstract":"<div><div>In this review we examine the neuroprotective potential of NAP (davunetide), a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP), in the context of neurodevelopmental and neurodegenerative disorders. ADNP, a protein essential for brain development and function, is associated with tauopathy-related diseases, such as Alzheimer’s Disease (AD), and circadian rhythm regulation. NAP enhances microtubule stability and prevents tauopathy. In preclinical studies, NAP shows promise in improving cognitive performance and correcting behavioral deficits in different models. Clinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated its safety, favorable bioavailability, and potential efficacy in improving cognitive function, making it a viable therapeutic option. In the pure tauopathy, progressive supranuclear palsy, NAP (davunetide) significantly slowed disease progression in women in a phase II-III clinical trial. Additionally, the complex interactions between ADNP, associated pathways, and circadian regulation and the extensive NAP compensation upon ADNP deficiency attest to further clinical development. Thus, NAP is an example of a reductionist approach in drug delivery, replacing/enhancing the critical large ADNP-related pathways including dysregulated microtubules and tauopathy with a small brain bioavailable investigational drug, davunetide.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"220 ","pages":"Article 115573"},"PeriodicalIF":15.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758150","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}
Pub Date : 2025-04-02DOI: 10.1016/j.addr.2025.115575
Rhearne Ryan , Mathew N. Leslie , Patrick He , Paul M. Young , Camilla M. Hoyos , Hui Xin Ong , Daniela Traini
Synchronisation of the suprachiasmatic nucleus (SCN) driven endogenous clock, located within the central nervous system (CNS), and exogenous time cues, is essential for maintaining circadian rhythmicity, homeostasis and overall wellbeing. Disordered circadian rhythms have been associated with various conditions, inclusive of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Traditional pharmacological approaches to circadian dysfunction in neurodegenerative disorders have primarily focused on oral drug delivery. Oral medications often face challenges in achieving the necessary systemic circulation to effectively bypass the blood brain barrier (BBB) and reach the CNS, primarily due to low or variable bioavailability. Advancements in non-invasive delivery methods, such as orally inhaled and intranasal formulations, present promising alternatives for targeting the CNS. Orally inhaled and intranasal drug delivery allows for medications to rapidly achieve high systemic circulation through increased bioavailability and fast onset of action. Additionally, intranasal delivery allows for therapies to bypass the BBB through the olfactory or trigeminal nerve pathways to directly enter the CNS. This review assesses the potential for orally inhaled and intranasal therapies to treat circadian disorders in neurodegenerative conditions. In addition, this review will explore melatonin as an example of enhancing therapeutic outcomes by adopting inhaled or intranasal drug delivery formulations to improve drug absorption and target circadian disorder more effectively.
{"title":"Intranasal and inhaled delivery systems for targeting circadian dysfunction in neurodegenerative disorders, perspective and future outlook","authors":"Rhearne Ryan , Mathew N. Leslie , Patrick He , Paul M. Young , Camilla M. Hoyos , Hui Xin Ong , Daniela Traini","doi":"10.1016/j.addr.2025.115575","DOIUrl":"10.1016/j.addr.2025.115575","url":null,"abstract":"<div><div>Synchronisation of the suprachiasmatic nucleus (SCN) driven endogenous clock, located within the central nervous system (CNS), and exogenous time cues, is essential for maintaining circadian rhythmicity, homeostasis and overall wellbeing. Disordered circadian rhythms have been associated with various conditions, inclusive of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Traditional pharmacological approaches to circadian dysfunction in neurodegenerative disorders have primarily focused on oral drug delivery. Oral medications often face challenges in achieving the necessary systemic circulation to effectively bypass the blood brain barrier (BBB) and reach the CNS, primarily due to low or variable bioavailability. Advancements in non-invasive delivery methods, such as orally inhaled and intranasal formulations, present promising alternatives for targeting the CNS. Orally inhaled and intranasal drug delivery allows for medications to rapidly achieve high systemic circulation through increased bioavailability and fast onset of action. Additionally, intranasal delivery allows for therapies to bypass the BBB through the olfactory or trigeminal nerve pathways to directly enter the CNS. This review assesses the potential for orally inhaled and intranasal therapies to treat circadian disorders in neurodegenerative conditions. In addition, this review will explore melatonin as an example of enhancing therapeutic outcomes by adopting inhaled or intranasal drug delivery formulations to improve drug absorption and target circadian disorder more effectively.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"220 ","pages":"Article 115575"},"PeriodicalIF":15.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758149","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}
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