Pub Date : 2026-04-01Epub Date: 2026-01-31DOI: 10.1016/j.addr.2026.115792
Claudia Muñoz Villaescusa , Diana van der Ven , Miguel A. Quetzeri-Santiago , David Fernandez Rivas
A comprehensive understanding of tissue mechanics at the microscale is critical for advancing personalised therapies, controlled drug release, and tissue engineering. Characterising the mechanical properties of complex, soft biological materials—particularly multilayered and anisotropic organs such as the skin and eye—remains a significant challenge due to their variable water content and scale-dependent behaviour. Traditional continuum models and linear material responses often fail to capture the dynamic and nonlinear nature of these tissues under physiologically relevant conditions.
This review provides a strategic overview of state-of-the-art techniques for probing the mechanical properties of soft biological tissues, with a focus on skin and ocular systems. Our focus on the skin and eye reflects their favourable barrier properties for topical drug delivery. We examine visualisation methods including optical imaging, interferometry, digital image correlation, optical coherence microscopy, and acoustic imaging. In parallel, we assess actuation mechanisms such as indentation, cavitation rheology, and flow elastography, highlighting their suitability for in vivo applications. Each technique is benchmarked against key operational parameters—spatial resolution, acquisition rate, invasiveness, and strain rate—relevant to drug delivery and therapeutic engineering.
By mapping the landscape of mechanical characterisation tools, this work offers a valuable resource for researchers in biomedical engineering and beyond, including fields such as physics and chemistry, where accurate dynamic analysis of soft complex materials is essential.
{"title":"A strategic guide of techniques for biomedical and tissue engineering applications to measure mechanical properties of soft matter, eye and skin","authors":"Claudia Muñoz Villaescusa , Diana van der Ven , Miguel A. Quetzeri-Santiago , David Fernandez Rivas","doi":"10.1016/j.addr.2026.115792","DOIUrl":"10.1016/j.addr.2026.115792","url":null,"abstract":"<div><div>A comprehensive understanding of tissue mechanics at the microscale is critical for advancing personalised therapies, controlled drug release, and tissue engineering. Characterising the mechanical properties of complex, soft biological materials—particularly multilayered and anisotropic organs such as the skin and eye—remains a significant challenge due to their variable water content and scale-dependent behaviour. Traditional continuum models and linear material responses often fail to capture the dynamic and nonlinear nature of these tissues under physiologically relevant conditions.</div><div>This review provides a strategic overview of state-of-the-art techniques for probing the mechanical properties of soft biological tissues, with a focus on skin and ocular systems. Our focus on the skin and eye reflects their favourable barrier properties for topical drug delivery. We examine visualisation methods including optical imaging, interferometry, digital image correlation, optical coherence microscopy, and acoustic imaging. In parallel, we assess actuation mechanisms such as indentation, cavitation rheology, and flow elastography, highlighting their suitability for <em>in vivo</em> applications. Each technique is benchmarked against key operational parameters—spatial resolution, acquisition rate, invasiveness, and strain rate—relevant to drug delivery and therapeutic engineering.</div><div>By mapping the landscape of mechanical characterisation tools, this work offers a valuable resource for researchers in biomedical engineering and beyond, including fields such as physics and chemistry, where accurate dynamic analysis of soft complex materials is essential.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"231 ","pages":"Article 115792"},"PeriodicalIF":17.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095684","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 : 2026-03-19DOI: 10.1016/j.addr.2026.115858
Fiona Halbig, Simon Reiländer, Christoph Keßler, David Ort, Wolfgang Schmehl, Josef Kehrein, Marcus Gutmann, Christof Däubler, Maximilian Michel, Robert Witte, Holger Braunschweig, Lorenz Meinel
Carbon monoxide (CO) has gained increasing attention as an endogenous gasotransmitter with potential therapeutic relevance. In preclinical studies, including acute lung injury, sepsis, transplantation, inflammatory bowel, and cardiovascular diseases, CO has shown anti-inflammatory, anti-apoptotic, vasodilatory, and cytoprotective properties, suggesting its application in treating a wide range of diseases associated with cellular stress. CO impairs blood oxygen transport when systemic exposure occurs, but it is safe when blood oxygen transport is not compromised. Consequently, treatment modalities benefit from local rather than systemic CO delivery to open the therapeutic window of this physiological gasotransmitter. This review, therefore, focuses on local drug delivery strategies for generating and delivering CO, and on solutions and perspectives for various applications that leverage CO's anti-inflammatory and cytoprotective effects with an enhanced safety profile. We present the use of CO-releasing molecules (CORMs) and their incorporation into advanced drug delivery devices to control local CO exposure. Special emphasis is placed on drug vehicles featuring controlled on-target delivery, dosing, and biocompatibility. Therefore, we identify key principles and remaining obstacles in CO delivery technologies, which confluences in strategies that reduce the risk for pharmaceutical development and clinical application for safe, controlled, and targeted therapies.
{"title":"From canes to pills: the evolution of carbon monoxide therapeutics.","authors":"Fiona Halbig, Simon Reiländer, Christoph Keßler, David Ort, Wolfgang Schmehl, Josef Kehrein, Marcus Gutmann, Christof Däubler, Maximilian Michel, Robert Witte, Holger Braunschweig, Lorenz Meinel","doi":"10.1016/j.addr.2026.115858","DOIUrl":"https://doi.org/10.1016/j.addr.2026.115858","url":null,"abstract":"<p><p>Carbon monoxide (CO) has gained increasing attention as an endogenous gasotransmitter with potential therapeutic relevance. In preclinical studies, including acute lung injury, sepsis, transplantation, inflammatory bowel, and cardiovascular diseases, CO has shown anti-inflammatory, anti-apoptotic, vasodilatory, and cytoprotective properties, suggesting its application in treating a wide range of diseases associated with cellular stress. CO impairs blood oxygen transport when systemic exposure occurs, but it is safe when blood oxygen transport is not compromised. Consequently, treatment modalities benefit from local rather than systemic CO delivery to open the therapeutic window of this physiological gasotransmitter. This review, therefore, focuses on local drug delivery strategies for generating and delivering CO, and on solutions and perspectives for various applications that leverage CO's anti-inflammatory and cytoprotective effects with an enhanced safety profile. We present the use of CO-releasing molecules (CORMs) and their incorporation into advanced drug delivery devices to control local CO exposure. Special emphasis is placed on drug vehicles featuring controlled on-target delivery, dosing, and biocompatibility. Therefore, we identify key principles and remaining obstacles in CO delivery technologies, which confluences in strategies that reduce the risk for pharmaceutical development and clinical application for safe, controlled, and targeted therapies.</p>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":" ","pages":"115858"},"PeriodicalIF":17.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493526","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 : 2026-03-15DOI: 10.1016/j.addr.2026.115854
Zhaoxi Zheng, Harshil K. Renawala, W. Peter Wuelfing, Nicole Buist, Izzat Raheem, Aaron Cote, Jeffrey C. Givand, Sandra B. Gabelli, Rubi Burlage, Allen C. Templeton, Guangli Hu, Yongchao Su
The paradigm for administering protein biologics is increasingly shifting from intravenous infusion to high-concentration subcutaneous delivery, driven by the desire for patient-centric, sometimes self-administered therapies to better manage chronic diseases. However, this trend is constrained by the inter-related biophysical challenges of protein instability and high viscosity that typically emerge at protein concentrations exceeding 100 mg/mL. In this review, we elucidate the underlying mechanisms of protein instability in a molecularly crowded environment of high-concentration formulations, wherein the close proximity of molecules affect protein structure and function through complex, and often competing, interplay of steric excluded volume repulsion and soft interactions including electrostatic, hydrogen-bonding and hydrophobic forces, leading to reversible and irreversible self-association, increased viscosity and meta-stable association pathways such as liquid-liquid phase separation. Consequently, manipulation of these competing intermolecular interactions can enable the development of stable high-concentration protein therapeutics through rational molecular and formulation design approaches that preserve the native state and elevate the energy barrier for aggregation. Here, we explore the multi-faceted strategies to achieve this balance, including rational formulation design with buffers, excipients, and innovative viscosity-reducing agents, alongside protein engineering approaches to create inherently developable molecules. Moreover, the molecular determinants of solution viscosity arising from protein-protein interactions are discussed with particular focus on the role of arginine and its derivatives to disrupt these network-forming interactions and reduce viscosity in a concentration-dependent manner. The discussion extends to advanced delivery strategies, such as non-aqueous protein powder suspensions and aqueous crystalline or amorphous formulations, which circumvent traditional viscosity limits, in part, by reducing bulk solution protein-protein interactions. Finally, the critical interface between drug product and delivery device is examined, highlighting device innovations that enable the injection of viscous liquids and addressing stability risks from silicone oil and metal leachables in prefilled syringes. Ultimately, the successful development of stable, deliverable, high-concentration biologics combination drug products requires an integrated approach that combines mechanistic understanding, protein biophysics, formulation science, and device engineering.
{"title":"Protein stability and Viscosity in molecularly crowded high-concentration biologics","authors":"Zhaoxi Zheng, Harshil K. Renawala, W. Peter Wuelfing, Nicole Buist, Izzat Raheem, Aaron Cote, Jeffrey C. Givand, Sandra B. Gabelli, Rubi Burlage, Allen C. Templeton, Guangli Hu, Yongchao Su","doi":"10.1016/j.addr.2026.115854","DOIUrl":"https://doi.org/10.1016/j.addr.2026.115854","url":null,"abstract":"The paradigm for administering protein biologics is increasingly shifting from intravenous infusion to high-concentration subcutaneous delivery, driven by the desire for patient-centric, sometimes self-administered therapies to better manage chronic diseases. However, this trend is constrained by the inter-related biophysical challenges of protein instability and high viscosity that typically emerge at protein concentrations exceeding 100 mg/mL. In this review, we elucidate the underlying mechanisms of protein instability in a molecularly crowded environment of high-concentration formulations, wherein the close proximity of molecules affect protein structure and function through complex, and often competing, interplay of steric excluded volume repulsion and soft interactions including electrostatic, hydrogen-bonding and hydrophobic forces, leading to reversible and irreversible self-association, increased viscosity and meta-stable association pathways such as liquid-liquid phase separation. Consequently, manipulation of these competing intermolecular interactions can enable the development of stable high-concentration protein therapeutics through rational molecular and formulation design approaches that preserve the native state and elevate the energy barrier for aggregation. Here, we explore the multi-faceted strategies to achieve this balance, including rational formulation design with buffers, excipients, and innovative viscosity-reducing agents, alongside protein engineering approaches to create inherently developable molecules. Moreover, the molecular determinants of solution viscosity arising from protein-protein interactions are discussed with particular focus on the role of arginine and its derivatives to disrupt these network-forming interactions and reduce viscosity in a concentration-dependent manner. The discussion extends to advanced delivery strategies, such as non-aqueous protein powder suspensions and aqueous crystalline or amorphous formulations, which circumvent traditional viscosity limits, in part, by reducing bulk solution protein-protein interactions. Finally, the critical interface between drug product and delivery device is examined, highlighting device innovations that enable the injection of viscous liquids and addressing stability risks from silicone oil and metal leachables in prefilled syringes. Ultimately, the successful development of stable, deliverable, high-concentration biologics combination drug products requires an integrated approach that combines mechanistic understanding, protein biophysics, formulation science, and device engineering.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"93 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454643","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 : 2026-03-13DOI: 10.1016/j.addr.2026.115855
Youssef Abdalla, Laxmi Prasanna Nandiraju, Haoran Yue, Conor Beaupres De Monsales, Charlotte Yeung, Abdul W. Basit
{"title":"Artificial intelligence-enabled personalisation of oral drug delivery: From data-driven design to on-demand manufacturing","authors":"Youssef Abdalla, Laxmi Prasanna Nandiraju, Haoran Yue, Conor Beaupres De Monsales, Charlotte Yeung, Abdul W. Basit","doi":"10.1016/j.addr.2026.115855","DOIUrl":"https://doi.org/10.1016/j.addr.2026.115855","url":null,"abstract":"","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"21 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447243","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 : 2026-03-13DOI: 10.1016/j.addr.2026.115856
Hao Lou, Yilue Zhang
{"title":"Emerging techniques for modeling and simulating subcutaneous injection and fate of drugs after injection","authors":"Hao Lou, Yilue Zhang","doi":"10.1016/j.addr.2026.115856","DOIUrl":"https://doi.org/10.1016/j.addr.2026.115856","url":null,"abstract":"","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"94 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447225","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 : 2026-03-11DOI: 10.1016/j.addr.2026.115851
Cher J.S. Liu, Shao-Bo Wang, Pin-Yu Su, Yuan-Pang Hsieh, Hsiang-Yu Wang
Intracellular delivery of therapeutic biomolecules represents a fundamental prerequisite for cell-based therapies and precision medicine, yet existing delivery methods present critical limitations. Viral vectors, while effective, pose safety risks including immunogenicity and insertional mutagenesis. Bulk electroporation offers a non-viral alternative but suffers from high cytotoxicity, heterogeneous electric field distributions, and poor efficiency in primary cells due to excessive voltage requirements and uncontrolled Joule heating.Microfluidic electroporation exploits microscale physics to decouple transfection efficiency from cell viability. By reducing electrode spacing to micrometers, these platforms achieve necessary field strengths at voltages below 50 V, minimizing Joule heating and electrolysis byproducts that plague bulk methods. Static platforms, including nanostructure-assisted designs, provide subcellular precision through localized field enhancement and real-time impedance monitoring, enabling mechanistic investigation of pore formation dynamics. Continuous-flow systems transform electroporation into a scalable manufacturing process, achieving throughputs of 108–109 cells per minute required for clinical cell therapy production while maintaining viabilities above 90% through hydrodynamic focusing and optimized channel geometries.Despite these engineering advances, systematic benchmarking against Current Good Manufacturing Practice (cGMP)-compliant commercial electroporators reveals critical translational barriers: reliance on research-grade polydimethylsiloxane instead of medical-grade thermoplastics, open manual workflows incompatible with sterile closed-system requirements, lack of validated process control protocols, and insufficient biological verification beyond transient fluorescent protein expression. Furthermore, cargo-specific constraints, including nuclear transport requirements for plasmid DNA versus ribonucleoprotein complexes and distinctions between transient mRNA expression versus permanent CRISPR/Cas9 genomic integration, demand fundamentally different optimization strategies rarely addressed in device-focused studies. Establishing microfluidic electroporation as a viable clinical platform requires integrated manufacturing modules coupling electroporation with upstream buffer exchange and downstream cell sorting, along with implementation of real-time process analytical technology and closed-loop artificial intelligence-driven control. Early regulatory engagement to establish Drug Master File pathways will enable broad therapeutic applications.
{"title":"Microfluidic electroporation for drug and gene delivery: Driving innovation from single-cell precision to high-throughput preclinical and therapeutic platforms","authors":"Cher J.S. Liu, Shao-Bo Wang, Pin-Yu Su, Yuan-Pang Hsieh, Hsiang-Yu Wang","doi":"10.1016/j.addr.2026.115851","DOIUrl":"https://doi.org/10.1016/j.addr.2026.115851","url":null,"abstract":"Intracellular delivery of therapeutic biomolecules represents a fundamental prerequisite for cell-based therapies and precision medicine, yet existing delivery methods present critical limitations. Viral vectors, while effective, pose safety risks including immunogenicity and insertional mutagenesis. Bulk electroporation offers a non-viral alternative but suffers from high cytotoxicity, heterogeneous electric field distributions, and poor efficiency in primary cells due to excessive voltage requirements and uncontrolled Joule heating.Microfluidic electroporation exploits microscale physics to decouple transfection efficiency from cell viability. By reducing electrode spacing to micrometers, these platforms achieve necessary field strengths at voltages below 50 V, minimizing Joule heating and electrolysis byproducts that plague bulk methods. Static platforms, including nanostructure-assisted designs, provide subcellular precision through localized field enhancement and real-time impedance monitoring, enabling mechanistic investigation of pore formation dynamics. Continuous-flow systems transform electroporation into a scalable manufacturing process, achieving throughputs of 10<sup>8</sup>–10<sup>9</sup> cells per minute required for clinical cell therapy production while maintaining viabilities above 90% through hydrodynamic focusing and optimized channel geometries.Despite these engineering advances, systematic benchmarking against Current Good Manufacturing Practice (cGMP)-compliant commercial electroporators reveals critical translational barriers: reliance on research-grade polydimethylsiloxane instead of medical-grade thermoplastics, open manual workflows incompatible with sterile closed-system requirements, lack of validated process control protocols, and insufficient biological verification beyond transient fluorescent protein expression. Furthermore, cargo-specific constraints, including nuclear transport requirements for plasmid DNA versus ribonucleoprotein complexes and distinctions between transient mRNA expression versus permanent CRISPR/Cas9 genomic integration, demand fundamentally different optimization strategies rarely addressed in device-focused studies. Establishing microfluidic electroporation as a viable clinical platform requires integrated manufacturing modules coupling electroporation with upstream buffer exchange and downstream cell sorting, along with implementation of real-time process analytical technology and closed-loop artificial intelligence-driven control. Early regulatory engagement to establish Drug Master File pathways will enable broad therapeutic applications.","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"7 1","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393483","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 : 2026-03-01Epub Date: 2026-01-09DOI: 10.1016/j.addr.2026.115775
Zhongliang Fu , Meichen Pan , Chunrong Yang , Hongwei Hou , Jinghong Li
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that hijack the ubiquitin-proteasome system to catalytically degrade pathogenic proteins. With the ability to target “undruggable” proteins and exert sustained pharmacological effects, PROTACs hold considerable promise for cancer therapy. However, achieving tumor-selective protein degradation remains a central challenge. This review outlines the application of PROTACs in cancer treatment and systematically summarizes emerging strategies to enhance tumor specificity. These approaches leverage hallmark features of tumors, distinctive surface biomarkers and a unique tumor microenvironment (TME), and are broadly categorized into two classes: active targeting, which employs tumor-selective ligands to enrich PROTACs in malignant cells; and conditionally activated strategies, where TME cues either selectively trigger PROTAC prodrugs or induce structural transformations in nanocarriers to enhance drug accumulation at the tumor site. By elucidating these mechanisms, we aim to bridge medicinal chemistry and intelligent nanomedicine, underpinning the tumor-selective protein degradation strategies and offering perspectives on future research directions to improve the biodistribution, safety, and therapeutic efficacy of next-generation PROTACs.
{"title":"Rational modification of PROTACs for tumor-selective protein degradation","authors":"Zhongliang Fu , Meichen Pan , Chunrong Yang , Hongwei Hou , Jinghong Li","doi":"10.1016/j.addr.2026.115775","DOIUrl":"10.1016/j.addr.2026.115775","url":null,"abstract":"<div><div>Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that hijack the ubiquitin-proteasome system to catalytically degrade pathogenic proteins. With the ability to target “undruggable” proteins and exert sustained pharmacological effects, PROTACs hold considerable promise for cancer therapy. However, achieving tumor-selective protein degradation remains a central challenge. This review outlines the application of PROTACs in cancer treatment and systematically summarizes emerging strategies to enhance tumor specificity. These approaches leverage hallmark features of tumors, distinctive surface biomarkers and a unique tumor microenvironment (TME), and are broadly categorized into two classes: active targeting, which employs tumor-selective ligands to enrich PROTACs in malignant cells; and conditionally activated strategies, where TME cues either selectively trigger PROTAC prodrugs or induce structural transformations in nanocarriers to enhance drug accumulation at the tumor site. By elucidating these mechanisms, we aim to bridge medicinal chemistry and intelligent nanomedicine, underpinning the tumor-selective protein degradation strategies and offering perspectives on future research directions to improve the biodistribution, safety, and therapeutic efficacy of next-generation PROTACs.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"230 ","pages":"Article 115775"},"PeriodicalIF":17.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949886","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}
Posterior segment ocular diseases (e.g., age-related macular degeneration and diabetic retinopathy, etc.) often necessitate frequent intravitreal (IVT) injections of biologics, due to the rapid drug clearance and formidable ocular barriers. While molecular engineering strategies and high-concentration protein formulations could extend the administration intervals to a certain extent, they are confronted with critical challenges, protein aggregation, high viscosity, and limited duration. This has spurred the development of innovative biologics-device combination products, which represent a paradigm shift towards prolonged therapy. This comprehensive review examines the latest advancements of these combination platforms, including refillable implants (e.g., SUSVIMO®), encapsulated cell technology (e.g., ENCELTO™), and recombinant adeno-associated virus (rAAV) vectors (e.g., LUXTURNA®). The progress in biologics - device combination technologies has significantly reduced the frequency of ocular injections. However, substantial hurdles, such as instability caused by material-biologics interactions, potential risks during the sterilization and manufacturing processes, safety risks, and the evolving regulatory landscape, still need to be addressed. Achieving a balance between the stability of biologics and advanced device design, enhancing long-term safety, and developing responsive smart systems with real-time monitoring and feedback capabilities remain crucial for the advancement of next-generation ophthalmic therapies.
{"title":"Biologics-device combinations: Enabling prolonged therapies in the posterior segment ocular disease","authors":"Shuqian Zhu , Jianjun Zhang , Xuling Jiang , Cheng Peng , Huiqin Liu , Feng Qian","doi":"10.1016/j.addr.2026.115773","DOIUrl":"10.1016/j.addr.2026.115773","url":null,"abstract":"<div><div>Posterior segment ocular diseases (e.g., age-related macular degeneration and diabetic retinopathy, etc.) often necessitate frequent intravitreal (IVT) injections of biologics, due to the rapid drug clearance and formidable ocular barriers. While molecular engineering strategies and high-concentration protein formulations could extend the administration intervals to a certain extent, they are confronted with critical challenges, protein aggregation, high viscosity, and limited duration. This has spurred the development of innovative biologics-device combination products, which represent a paradigm shift towards prolonged therapy. This comprehensive review examines the latest advancements of these combination platforms, including refillable implants (e.g., SUSVIMO®), encapsulated cell technology (e.g., ENCELTO™), and recombinant adeno-associated virus (rAAV) vectors (e.g., LUXTURNA®). The progress in biologics - device combination technologies has significantly reduced the frequency of ocular injections. However, substantial hurdles, such as instability caused by material-biologics interactions, potential risks during the sterilization and manufacturing processes, safety risks, and the evolving regulatory landscape, still need to be addressed. Achieving a balance between the stability of biologics and advanced device design, enhancing long-term safety, and developing responsive smart systems with real-time monitoring and feedback capabilities remain crucial for the advancement of next-generation ophthalmic therapies.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"230 ","pages":"Article 115773"},"PeriodicalIF":17.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920277","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 : 2026-03-01Epub Date: 2026-01-15DOI: 10.1016/j.addr.2026.115778
Hye Jin Lee , Yunxuan Xie , Colin F. Greineder , Peter M. Tessier
Oligonucleotide therapeutics, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have gained increasing attention as a novel modality for gene-targeted interventions for central nervous system (CNS) disorders, particularly in the context of rare and inherited neurological conditions. By correcting pathogenic abnormalities in gene splicing or expression, oligonucleotide therapeutics offer a combination of extreme specificity and disease-modifying or even curative effects. However, achieving robust delivery to the CNS after systemic administration remains a significant challenge due to the presence of the blood-brain barrier and the intrinsic physicochemical limitations of oligonucleotide therapeutics, such as their large molecular size, high charge, and susceptibility to enzymatic degradation. Peptide-, antibody-, and lipid-based conjugates have emerged as versatile strategies for CNS oligonucleotide delivery, offering distinct advantages in molecular recognition, tunability, biocompatibility, and structural uniformity. Here, we review emerging design principles for engineering peptide, antibody, and lipid conjugates to enhance binding affinity, target selectivity, pharmacokinetics, and pharmacodynamics of oligonucleotide therapeutics for CNS applications. We also discuss how engineered delivery platforms have the potential to improve therapeutic efficacy across a spectrum of neurological disorders, from rare hereditary syndromes to highly prevalent neurodegenerative diseases.
{"title":"Bioconjugates for improved delivery of oligonucleotide therapeutics to the central nervous system","authors":"Hye Jin Lee , Yunxuan Xie , Colin F. Greineder , Peter M. Tessier","doi":"10.1016/j.addr.2026.115778","DOIUrl":"10.1016/j.addr.2026.115778","url":null,"abstract":"<div><div>Oligonucleotide therapeutics, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have gained increasing attention as a novel modality for gene-targeted interventions for central nervous system (CNS) disorders, particularly in the context of rare and inherited neurological conditions. By correcting pathogenic abnormalities in gene splicing or expression, oligonucleotide therapeutics offer a combination of extreme specificity and disease-modifying or even curative effects. However, achieving robust delivery to the CNS after systemic administration remains a significant challenge due to the presence of the blood-brain barrier and the intrinsic physicochemical limitations of oligonucleotide therapeutics, such as their large molecular size, high charge, and susceptibility to enzymatic degradation. Peptide-, antibody-, and lipid-based conjugates have emerged as versatile strategies for CNS oligonucleotide delivery, offering distinct advantages in molecular recognition, tunability, biocompatibility, and structural uniformity. Here, we review emerging design principles for engineering peptide, antibody, and lipid conjugates to enhance binding affinity, target selectivity, pharmacokinetics, and pharmacodynamics of oligonucleotide therapeutics for CNS applications. We also discuss how engineered delivery platforms have the potential to improve therapeutic efficacy across a spectrum of neurological disorders, from rare hereditary syndromes to highly prevalent neurodegenerative diseases.</div></div>","PeriodicalId":7254,"journal":{"name":"Advanced drug delivery reviews","volume":"230 ","pages":"Article 115778"},"PeriodicalIF":17.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993315","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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