Pub Date : 2025-12-02DOI: 10.1016/j.biomaterials.2025.123886
Xingbang Ruan , Yingchuang Tang , Kai Zhang , Junxin Zhang , Liang Qiu , Yihan Shi , Xiangyan Zhen , Shiyu Yu , Luxin Wei , Huilin Yang , Hanwen Li , Bin Li , Kangwu Chen
The treatment of severe bone defects remains a critical clinical challenge. The primary factor underlying impaired healing is the absence of periosteum and osteogenic blood vessels at the defect site. During the early stages of bone regeneration, elevated levels of reactive oxygen species (ROS) are commonly observed, which harms mitochondrial function and osteogenic effect. Here, we developed a microenvironment-responsive trilayered bionic periosteum (NMC@POB) designed to sequentially promote bone regeneration via osteogenic-angiogenic coupling. This construct features an outer layer of collagen embedded with tannic acid-cerium nanozymes (TA-Ce NMs) to scavenge ROS and restore redox homeostasis, a middle polylactic acid (PLA) layer for structural support, and an inner core of oxidized xyloglucan-loaded bone morphogenetic protein-2 (OXG-BMP2) to provide sustained osteo-inductive cues. In vitro and in vivo evaluations demonstrated that NMC@POB effectively reduced oxidative stress, enhanced mitochondrial function, and promoted coordinated osteogenesis and angiogenesis in a rat calvarial defect model. Transcriptomic analysis further revealed significant activation of the Wnt/β-catenin pathway, contributing to the upregulation of genes involved in both bone formation and neovascularization. Collectively, this trilayered periosteum offers a bionic and microenvironment-responsive strategy for orchestrated bone regeneration in challenging defect.
{"title":"Microenvironment-responsive trilayered bionic periosteum enhances osteogenic-angiogenic coupling for sequential bone regeneration","authors":"Xingbang Ruan , Yingchuang Tang , Kai Zhang , Junxin Zhang , Liang Qiu , Yihan Shi , Xiangyan Zhen , Shiyu Yu , Luxin Wei , Huilin Yang , Hanwen Li , Bin Li , Kangwu Chen","doi":"10.1016/j.biomaterials.2025.123886","DOIUrl":"10.1016/j.biomaterials.2025.123886","url":null,"abstract":"<div><div>The treatment of severe bone defects remains a critical clinical challenge. The primary factor underlying impaired healing is the absence of periosteum and osteogenic blood vessels at the defect site. During the early stages of bone regeneration, elevated levels of reactive oxygen species (ROS) are commonly observed, which harms mitochondrial function and osteogenic effect. Here, we developed a microenvironment-responsive trilayered bionic periosteum (NMC@POB) designed to sequentially promote bone regeneration <em>via</em> osteogenic-angiogenic coupling. This construct features an outer layer of collagen embedded with tannic acid-cerium nanozymes (TA-Ce NMs) to scavenge ROS and restore redox homeostasis, a middle polylactic acid (PLA) layer for structural support, and an inner core of oxidized xyloglucan-loaded bone morphogenetic protein-2 (OXG-BMP2) to provide sustained osteo-inductive cues. <em>In vitro</em> and <em>in vivo</em> evaluations demonstrated that NMC@POB effectively reduced oxidative stress, enhanced mitochondrial function, and promoted coordinated osteogenesis and angiogenesis in a rat calvarial defect model. Transcriptomic analysis further revealed significant activation of the Wnt/β-catenin pathway, contributing to the upregulation of genes involved in both bone formation and neovascularization. Collectively, this trilayered periosteum offers a bionic and microenvironment-responsive strategy for orchestrated bone regeneration in challenging defect.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123886"},"PeriodicalIF":12.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686668","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 : 2025-12-01DOI: 10.1016/j.biomaterials.2025.123882
Yefeng Wang , Siwen Wu , Yilin He , Jiani Zhang , Yujiao Chen , Lei Zhou , Xiaopeng Li , Li Yang
To enable Small Interfering RNA (siRNA) transdermal delivery, we use computational modeling to predict key properties of four cationic peptide carriers. These parameters can be utilized for the prediction of peptide carrier diffusion within the stratum corneum, thereby facilitating the screening of carriers with transdermal delivery capabilities. We take this opportunity to examine the discrepancy between computer-simulated transdermal vehicle functions and actual therapeutic efficacy. We validate the therapeutic efficacy of four peptide carriers by employing both human cell-derived 3D skin models and a murine psoriasis model. To advance clinical applications, we developed a skin-adhesive spray that contains peptide carriers loaded with ADAM17-targeting siRNA. Following penetration into the dermis, the siRNA-loaded carriers are internalized by immune cells, downregulating a disintegrin and metalloproteinase 17 (ADAM17) protein expression. This consequently suppresses Tumor Necrosis Factor-α (TNF-α)-mediated inflammatory responses and ameliorates psoriatic pathology. Finally, by employing multiplex immunofluorescence imaging to visualize the spatial proximity between epithelial and immune cells, we elucidate their functional cross-talk within the tissue microenvironment. The findings demonstrate that our computer-optimized peptide carrier achieves transdermal siRNA delivery and reprograms the psoriasis-associated inflammatory microenvironment.
{"title":"In silico optimized cell-penetrating peptides achieve transdermal siRNA delivery and regulate inflammatory environment in psoriasis","authors":"Yefeng Wang , Siwen Wu , Yilin He , Jiani Zhang , Yujiao Chen , Lei Zhou , Xiaopeng Li , Li Yang","doi":"10.1016/j.biomaterials.2025.123882","DOIUrl":"10.1016/j.biomaterials.2025.123882","url":null,"abstract":"<div><div>To enable Small Interfering RNA (siRNA) transdermal delivery, we use computational modeling to predict key properties of four cationic peptide carriers. These parameters can be utilized for the prediction of peptide carrier diffusion within the stratum corneum, thereby facilitating the screening of carriers with transdermal delivery capabilities. We take this opportunity to examine the discrepancy between computer-simulated transdermal vehicle functions and actual therapeutic efficacy. We validate the therapeutic efficacy of four peptide carriers by employing both human cell-derived 3D skin models and a murine psoriasis model. To advance clinical applications, we developed a skin-adhesive spray that contains peptide carriers loaded with ADAM17-targeting siRNA. Following penetration into the dermis, the siRNA-loaded carriers are internalized by immune cells, downregulating a disintegrin and metalloproteinase 17 (ADAM17) protein expression. This consequently suppresses Tumor Necrosis Factor-α (TNF-α)-mediated inflammatory responses and ameliorates psoriatic pathology. Finally, by employing multiplex immunofluorescence imaging to visualize the spatial proximity between epithelial and immune cells, we elucidate their functional cross-talk within the tissue microenvironment. The findings demonstrate that our computer-optimized peptide carrier achieves transdermal siRNA delivery and reprograms the psoriasis-associated inflammatory microenvironment.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123882"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145675898","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 : 2025-12-01DOI: 10.1016/j.biomaterials.2025.123873
Sujin Noh , Yong Jun Jin , Dong Il Shin , Hyeon Jae Kwon , Hee-Woong Yun , Soon Hee Kim , Jae-Young Park , Jun Young Chung , Sumin Lim , Do Young Park
Despite recent advances, clinical translation of articular cartilage remains limited. This is primarily due to engineering challenges and safety issues associated with extensive post-printing steps, including the reliance on exogenous growth factors and cross-linking agents. To overcome these limitations, we developed a high-performance cartilage Tissue bioink incorporating porcine synovium-derived mesenchymal stem cell (pSMSCs) mesenchymal condensation process augmented by decellularized cartilage extracellular matrix (DCECM) to facilitate intrinsic chondrogenesis without additional biochemical cues. The Tissue bioink exhibited a homogeneous distribution of pSMSCs and DCECM, with increase in cartilage-specific ECM components. Proteomic analysis further demonstrated increased cartilage ECM components and pathways associated with matrix remodeling and chondrogenesis via TGF-β1/SMAD signaling axis. Rheological analysis confirmed that the bioink exhibited shear-thinning behavior and rapid recovery of structural integrity, ensuring stable printability. Optimized printing parameters supported high cell viability. After 14 days of culture without growth factors or cross-linking agents, the printed constructs exhibited a twofold increase in sulfated glycosaminoglycan and collagen deposition, further validating their ongoing chondrogenic potential. In a porcine full-thickness cartilage defect model, Tissue bioink-printed constructs promoted robust cartilage regeneration, demonstrating enhanced ECM deposition, histological cartilage characteristics, and significantly improved biomechanical properties (p < 0.001) at six months. Furthermore, PKH-26-labeled pSMSCs persisted within the defect site, indicating sustained cellular viability and potential contribution to tissue remodeling. These findings suggest that DCECM-augmented mesenchymal condensation provides a biomimetic biofabrication strategy that enhances chondrogenesis without the need for post-printing growth factors and cross-linking steps, presenting a promising approach for a clinically translatable cartilage repair.
{"title":"High-performance cartilage tissue bioink for 3D bioprinting with minimal post-processing for articular cartilage regeneration","authors":"Sujin Noh , Yong Jun Jin , Dong Il Shin , Hyeon Jae Kwon , Hee-Woong Yun , Soon Hee Kim , Jae-Young Park , Jun Young Chung , Sumin Lim , Do Young Park","doi":"10.1016/j.biomaterials.2025.123873","DOIUrl":"10.1016/j.biomaterials.2025.123873","url":null,"abstract":"<div><div>Despite recent advances, clinical translation of articular cartilage remains limited. This is primarily due to engineering challenges and safety issues associated with extensive post-printing steps, including the reliance on exogenous growth factors and cross-linking agents. To overcome these limitations, we developed a high-performance cartilage Tissue bioink incorporating porcine synovium-derived mesenchymal stem cell (pSMSCs) mesenchymal condensation process augmented by decellularized cartilage extracellular matrix (DCECM) to facilitate intrinsic chondrogenesis without additional biochemical cues. The Tissue bioink exhibited a homogeneous distribution of pSMSCs and DCECM, with increase in cartilage-specific ECM components. Proteomic analysis further demonstrated increased cartilage ECM components and pathways associated with matrix remodeling and chondrogenesis via TGF-β1/SMAD signaling axis. Rheological analysis confirmed that the bioink exhibited shear-thinning behavior and rapid recovery of structural integrity, ensuring stable printability. Optimized printing parameters supported high cell viability. After 14 days of culture without growth factors or cross-linking agents, the printed constructs exhibited a twofold increase in sulfated glycosaminoglycan and collagen deposition, further validating their ongoing chondrogenic potential. In a porcine full-thickness cartilage defect model, Tissue bioink-printed constructs promoted robust cartilage regeneration, demonstrating enhanced ECM deposition, histological cartilage characteristics, and significantly improved biomechanical properties (p < 0.001) at six months. Furthermore, PKH-26-labeled pSMSCs persisted within the defect site, indicating sustained cellular viability and potential contribution to tissue remodeling. These findings suggest that DCECM-augmented mesenchymal condensation provides a biomimetic biofabrication strategy that enhances chondrogenesis without the need for post-printing growth factors and cross-linking steps, presenting a promising approach for a clinically translatable cartilage repair.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123873"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760485","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 : 2025-11-30DOI: 10.1016/j.biomaterials.2025.123866
Ninon Möhl , Susan Babu , Camille Bonhomme , Ramin Nasehi , Matthias Mork , Tamás Haraszti , Gilles Wittmann , Baohu Wu , Rostislav Vinokur , Kyoohyun Kim , Rafael Kramann , Jochen Guck , Laura De Laporte
Anisometric rod-shaped microgels are promising building blocks for tissue engineering, offering injectability, porosity, macroscopic anisotropy, and biochemical functionality—key features for directing cell adhesion, growth, alignment, and interaction. The continuous production of thin or highly porous elongated microgels is therefore desirable, preferably offering control over their stiffness, size, and aspect ratio. We present advancements in compartmentalized jet polymerization, a microfluidic technique that generates microgels that are ten times narrower than the channel width by forming a polymer jet and crosslinking alternating segments with a pulsed laser. Originally limited to diameters of ∼8 μm, we have now refined the method to produce microgels as small as ∼3 μm. Additionally, we developed ultra-soft and ultra-porous microgels that swell to diameters of 50–120 μm with pore sizes in the range 2–5 μm. While the thin soft microgels can be employed in our Anisogel technology to combine injectability with magnetic alignment, the ultra-porous microgels would increase diffusion in our microporous annealed particle (MAP) scaffolds made from rod-shaped microgels. This paper focuses on the continuous production and characterization of rod microgels with properties that cannot be achieve with other methods. Furthermore, we report initial results of the microgels’ potential and challenges to be used inside an Anisogel, which was so far only possible with stiffer magneto-responsive microgels produced by an in-mold polymerization batch process, and to form MAPs by cell-induced assembly of the ultra-porous rods. Further studies will be required to fully exploit the potential of these unique microgels for tissue engineering applications.
{"title":"Exploring compartmentalized jet polymerization for novel rod-shaped microgels and their potential in tissue engineering applications","authors":"Ninon Möhl , Susan Babu , Camille Bonhomme , Ramin Nasehi , Matthias Mork , Tamás Haraszti , Gilles Wittmann , Baohu Wu , Rostislav Vinokur , Kyoohyun Kim , Rafael Kramann , Jochen Guck , Laura De Laporte","doi":"10.1016/j.biomaterials.2025.123866","DOIUrl":"10.1016/j.biomaterials.2025.123866","url":null,"abstract":"<div><div>Anisometric rod-shaped microgels are promising building blocks for tissue engineering, offering injectability, porosity, macroscopic anisotropy, and biochemical functionality—key features for directing cell adhesion, growth, alignment, and interaction. The continuous production of thin or highly porous elongated microgels is therefore desirable, preferably offering control over their stiffness, size, and aspect ratio. We present advancements in compartmentalized jet polymerization, a microfluidic technique that generates microgels that are ten times narrower than the channel width by forming a polymer jet and crosslinking alternating segments with a pulsed laser. Originally limited to diameters of ∼8 μm, we have now refined the method to produce microgels as small as ∼3 μm. Additionally, we developed ultra-soft and ultra-porous microgels that swell to diameters of 50–120 μm with pore sizes in the range 2–5 μm. While the thin soft microgels can be employed in our Anisogel technology to combine injectability with magnetic alignment, the ultra-porous microgels would increase diffusion in our microporous annealed particle (MAP) scaffolds made from rod-shaped microgels. This paper focuses on the continuous production and characterization of rod microgels with properties that cannot be achieve with other methods. Furthermore, we report initial results of the microgels’ potential and challenges to be used inside an Anisogel, which was so far only possible with stiffer magneto-responsive microgels produced by an in-mold polymerization batch process, and to form MAPs by cell-induced assembly of the ultra-porous rods. Further studies will be required to fully exploit the potential of these unique microgels for tissue engineering applications.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123866"},"PeriodicalIF":12.9,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686634","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 : 2025-11-27DOI: 10.1016/j.biomaterials.2025.123875
Haotian Qin , Zhenhai Xie , Yuanhao Wang , Chen Zhang , Binbin Wang , Peng Zhang , Guojiang Wan , Deli Wang , Junyu Qian
Bone fracture healing under inflammatory conditions remains a major clinical challenge due to immune dysregulation, impaired vascularization, delayed osteogenesis, and increased infection risk. Zinc-copper (ZnCu) alloys offer biodegradability, mechanical support, and bioactivity, but suffer from insufficient degradation rate, local cytotoxicity from burst Zn2+ release, and uneven corrosion. To address these issues, we constructed a dexamethasone-loaded metal-organic framework hybrid coating (DEX@ZIF-8) in situ on ZnCu intramedullary nails (IMNs) via hydrothermal oxidation and subsequent coordination-driven ZIF-8 assembly with DEX loading, enabling controllable drug release and adaptive degradation. Materials characterization confirmed a compact, well-adhered coating with a distinct hierarchical structure composed of uniformly distributed, polyhedral ZIF-8 crystals tightly integrated with the ZnCu substrate. Electrochemical and immersion results confirmed that the coating accelerated corrosion while maintaining uniform degradation, enabling controlled dual release of Zn2+ and DEX without local burst. In vitro, Zn2+ and DEX synergistically promoted macrophage polarization toward the anti-inflammatory M2 phenotype by up-regulating CD206 and Arg-1. Angiogenesis was enhanced through Zn2+-induced HIF-1α activation, while osteogenic differentiation was associated with PI3K/Akt and MAPK signaling, as confirmed by transcriptomic up-regulation of BMP-2, COL1A1, OPN. In a rat inflammatory femur fracture model, coated IMNs maintained mechanical integrity over 12 weeks and significantly accelerated bone regeneration without signs of fracture or local toxicity. This study offers a promising surface engineering approach for Zn-based IMNs to meet the complex demands of inflammatory bone repair.
{"title":"A hierarchical dexamethasone-loaded zeolitic imidazolate framework-8 hybrid coating on biodegradable ZnCu alloys for coordinated immuno-angiogenic-osteogenic and antibacterial regulation in inflammation-impaired fracture healing","authors":"Haotian Qin , Zhenhai Xie , Yuanhao Wang , Chen Zhang , Binbin Wang , Peng Zhang , Guojiang Wan , Deli Wang , Junyu Qian","doi":"10.1016/j.biomaterials.2025.123875","DOIUrl":"10.1016/j.biomaterials.2025.123875","url":null,"abstract":"<div><div>Bone fracture healing under inflammatory conditions remains a major clinical challenge due to immune dysregulation, impaired vascularization, delayed osteogenesis, and increased infection risk. Zinc-copper (ZnCu) alloys offer biodegradability, mechanical support, and bioactivity, but suffer from insufficient degradation rate, local cytotoxicity from burst Zn<sup>2+</sup> release, and uneven corrosion. To address these issues, we constructed a dexamethasone-loaded metal-organic framework hybrid coating (DEX@ZIF-8) in situ on ZnCu intramedullary nails (IMNs) via hydrothermal oxidation and subsequent coordination-driven ZIF-8 assembly with DEX loading, enabling controllable drug release and adaptive degradation. Materials characterization confirmed a compact, well-adhered coating with a distinct hierarchical structure composed of uniformly distributed, polyhedral ZIF-8 crystals tightly integrated with the ZnCu substrate. Electrochemical and immersion results confirmed that the coating accelerated corrosion while maintaining uniform degradation, enabling controlled dual release of Zn<sup>2+</sup> and DEX without local burst. <em>In vitro</em>, Zn<sup>2+</sup> and DEX synergistically promoted macrophage polarization toward the anti-inflammatory M2 phenotype by up-regulating CD206 and Arg-1. Angiogenesis was enhanced through Zn<sup>2+</sup>-induced HIF-1α activation, while osteogenic differentiation was associated with PI3K/Akt and MAPK signaling, as confirmed by transcriptomic up-regulation of BMP-2, COL1A1, OPN. In a rat inflammatory femur fracture model, coated IMNs maintained mechanical integrity over 12 weeks and significantly accelerated bone regeneration without signs of fracture or local toxicity. This study offers a promising surface engineering approach for Zn-based IMNs to meet the complex demands of inflammatory bone repair.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123875"},"PeriodicalIF":12.9,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690460","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 : 2025-11-27DOI: 10.1016/j.biomaterials.2025.123867
Inmaculada Conejos-Sánchez , Tetiana Melnyk , Esther Masiá , Daniel Morelló-Bolumar , Luz Tortajada-Comeche , Irene Dolz-Pérez , Lucía Inés Torrijos-Saiz , Paula Tenhaeff , Julia Roosz , Alessia Moruzzi , Gloria Sogorb , Maria Medel , Peter Loskill , Esther Roselló , Victor Sebastian , Helena Florindo , Carles Felip-León , Vicent J. Nebot , Vicente Herranz-Pérez , José Manuel García-Vedugo , María J. Vicent
Intranasal administration represents a safe and non-invasive route for drug delivery to the brain; however, clinical translation remains limited due to anatomical and physiological barriers. We present a modular hybrid biomaterial platform (NanoInBrain) that bypasses the blood-brain barrier via the olfactory route and enables central nervous system (CNS) drug delivery. The platform integrates a rationally designed polypeptide-based nanocarrier with a depot-forming hydrogel vehicle - a hyaluronic acid–poly-L-glutamate crosspolymer (HA-CP, Yalic®) - adapted from dermatological applications to enhance nasal mucosal retention and brain uptake. We engineered the nanocarrier system using star-shaped poly-L-glutamate (StPGA) architectures and systematically tuned physicochemical properties to optimize mucosal interaction and CNS diffusion. We introduced mucoadhesive and mucodiffusive functionalities via C-terminal odorranalectin (OL) conjugation, which improved nasal epithelium permeation through receptor-mediated mechanisms. Redox-responsive disulfide crosslinking (StPGA-CL-SS) further enhanced mucosal transport by enabling thiol-mediated anchoring to mucin glycoproteins, outperforming inert click-crosslinked variants. Ex vivo Franz diffusion studies and a nasal-mucosa-on-chip model demonstrated robust permeation, with in vivo imaging confirming brain distribution and intracellular uptake in neurons and microglia. Incorporation of HA-CP prolonged nasal residence (∼4 h) and increased total brain accumulation while being well-tolerated. This new platform combines architectural tunability, bioresponsive surface chemistry, and depot-mediated delivery in a scalable, biocompatible nose-to-brain delivery system with potential for treating neurological disorders.
{"title":"A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery","authors":"Inmaculada Conejos-Sánchez , Tetiana Melnyk , Esther Masiá , Daniel Morelló-Bolumar , Luz Tortajada-Comeche , Irene Dolz-Pérez , Lucía Inés Torrijos-Saiz , Paula Tenhaeff , Julia Roosz , Alessia Moruzzi , Gloria Sogorb , Maria Medel , Peter Loskill , Esther Roselló , Victor Sebastian , Helena Florindo , Carles Felip-León , Vicent J. Nebot , Vicente Herranz-Pérez , José Manuel García-Vedugo , María J. Vicent","doi":"10.1016/j.biomaterials.2025.123867","DOIUrl":"10.1016/j.biomaterials.2025.123867","url":null,"abstract":"<div><div>Intranasal administration represents a safe and non-invasive route for drug delivery to the brain; however, clinical translation remains limited due to anatomical and physiological barriers. We present a modular hybrid biomaterial platform (NanoInBrain) that bypasses the blood-brain barrier via the olfactory route and enables central nervous system (CNS) drug delivery. The platform integrates a rationally designed polypeptide-based nanocarrier with a depot-forming hydrogel vehicle - a hyaluronic acid–poly-L-glutamate crosspolymer (HA-CP, Yalic®) - adapted from dermatological applications to enhance nasal mucosal retention and brain uptake. We engineered the nanocarrier system using star-shaped poly-L-glutamate (StPGA) architectures and systematically tuned physicochemical properties to optimize mucosal interaction and CNS diffusion. We introduced mucoadhesive and mucodiffusive functionalities via C-terminal odorranalectin (OL) conjugation, which improved nasal epithelium permeation through receptor-mediated mechanisms. Redox-responsive disulfide crosslinking (StPGA-CL-SS) further enhanced mucosal transport by enabling thiol-mediated anchoring to mucin glycoproteins, outperforming inert click-crosslinked variants. <em>Ex vivo</em> Franz diffusion studies and a nasal-mucosa-on-chip model demonstrated robust permeation, with in vivo imaging confirming brain distribution and intracellular uptake in neurons and microglia. Incorporation of HA-CP prolonged nasal residence (∼4 h) and increased total brain accumulation while being well-tolerated. This new platform combines architectural tunability, bioresponsive surface chemistry, and depot-mediated delivery in a scalable, biocompatible nose-to-brain delivery system with potential for treating neurological disorders.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123867"},"PeriodicalIF":12.9,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690459","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 : 2025-11-25DOI: 10.1016/j.biomaterials.2025.123869
Erin M. O'Brien , Tina Tylek , Hannah C. Geisler , Alvin J. Mukalel , Ricardo C. Whitaker , Samuel Sung , Benjamin I. Binder-Markey , Drew Weissman , Michael J. Mitchell , Kara L. Spiller
The use of macrophage cell therapies is limited by their tendency to change phenotype in response to external cues in situ. Here we demonstrate that an optimized lipid nanoparticle (LNP) formulation effectively delivers IL4 mRNA to human and murine primary macrophages, resulting in rapid transfection, IL-4 secretion, and reparative phenotype modulation. In a model of murine volumetric muscle loss, adoptively transferred macrophages pre-treated with IL4-LNPs maintained a reparative phenotype for at least one week, despite the inflammatory injury microenvironment. IL4-LNP-treated macrophages also promoted a reparative phenotype in endogenous macrophages and supported muscle repair outcomes, including increased vascularization, fiber size distribution, and remodeling of the scaffold. T cell subtype in the muscle or the draining lymph node was not affected. The novel strategy established here may facilitate the control and use of macrophage cell therapies for other applications in regenerative medicine.
{"title":"Macrophage cell therapy enabled by interleukin-4 mRNA-loaded lipid nanoparticles to sustain a pro-reparative phenotype in inflammatory injuries","authors":"Erin M. O'Brien , Tina Tylek , Hannah C. Geisler , Alvin J. Mukalel , Ricardo C. Whitaker , Samuel Sung , Benjamin I. Binder-Markey , Drew Weissman , Michael J. Mitchell , Kara L. Spiller","doi":"10.1016/j.biomaterials.2025.123869","DOIUrl":"10.1016/j.biomaterials.2025.123869","url":null,"abstract":"<div><div>The use of macrophage cell therapies is limited by their tendency to change phenotype in response to external cues in situ. Here we demonstrate that an optimized lipid nanoparticle (LNP) formulation effectively delivers IL4 mRNA to human and murine primary macrophages, resulting in rapid transfection, IL-4 secretion, and reparative phenotype modulation. In a model of murine volumetric muscle loss, adoptively transferred macrophages pre-treated with IL4-LNPs maintained a reparative phenotype for at least one week, despite the inflammatory injury microenvironment. IL4-LNP-treated macrophages also promoted a reparative phenotype in endogenous macrophages and supported muscle repair outcomes, including increased vascularization, fiber size distribution, and remodeling of the scaffold. T cell subtype in the muscle or the draining lymph node was not affected. The novel strategy established here may facilitate the control and use of macrophage cell therapies for other applications in regenerative medicine.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123869"},"PeriodicalIF":12.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621096","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 : 2025-11-24DOI: 10.1016/j.biomaterials.2025.123858
Heng Zhou , Ping Wen , Ye Liu , Zhifei Ye , Wei Xiong , Yonghao Liu , Hanyu Ding , Xingxiang Duan , Yu Luo , Qiang Qin , Ruohan Li , Yan He , Shanping Mao , Qingsong Ye
{"title":"Corrigendum to “MiR-138 reprograms dental pulp stem cells into GABAergic neurons via the GATAD2B/MTA3/WNTs axis for stroke treatment” [Biomaterials 325 (2026) 123618]","authors":"Heng Zhou , Ping Wen , Ye Liu , Zhifei Ye , Wei Xiong , Yonghao Liu , Hanyu Ding , Xingxiang Duan , Yu Luo , Qiang Qin , Ruohan Li , Yan He , Shanping Mao , Qingsong Ye","doi":"10.1016/j.biomaterials.2025.123858","DOIUrl":"10.1016/j.biomaterials.2025.123858","url":null,"abstract":"","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"327 ","pages":"Article 123858"},"PeriodicalIF":12.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601606","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 : 2025-11-24DOI: 10.1016/j.biomaterials.2025.123870
Hassan Kanso , Stefania Di Cio , Ruth Rose , Isabel M. Palacios , Julien E. Gautrot
During early stages of development of cerebral organoids, budding neuroepithelia display striking changes in size and morphology, occurring very rapidly. Whilst mechanical forces mediated by cadherin-cadherin junctions are known to control the assembly, maturation and stability of epithelia, little is known of the mechanical context associated with neuroepithelial organoid development. In this report, we demonstrate a rapid translocation of YAP to budding neuroepithelial apical junctions, suggesting the build-up of strong compressive forces early on in their development. To study the mechanics of budding rosettes, we designed oil microdroplets stabilised by protein nanosheets displaying cadherin receptors, able to engage with receptors presented by neighbouring neuroepithelial cells, to integrate into embryoid bodies and developing organoids. The resulting artificial cells are able to sustain the formation of mature junctions with neighbouring cells and lead to the recruitment of tight junction maturation proteins such as ZO1. During early budding of neuroepithelial rosettes, artificial cells are found to be rapidly expelled from the developing organoids, further evidencing apical compressive forces. These forces are not opposed by sufficiently strong shear forces from neighbouring cells, or adhesive forces maintaining anchorage to the apical junction, to induce deformation of artificial cells.
{"title":"Artificial cells evidence apical compressive forces building up during neuroepithelial organoid early development","authors":"Hassan Kanso , Stefania Di Cio , Ruth Rose , Isabel M. Palacios , Julien E. Gautrot","doi":"10.1016/j.biomaterials.2025.123870","DOIUrl":"10.1016/j.biomaterials.2025.123870","url":null,"abstract":"<div><div>During early stages of development of cerebral organoids, budding neuroepithelia display striking changes in size and morphology, occurring very rapidly. Whilst mechanical forces mediated by cadherin-cadherin junctions are known to control the assembly, maturation and stability of epithelia, little is known of the mechanical context associated with neuroepithelial organoid development. In this report, we demonstrate a rapid translocation of YAP to budding neuroepithelial apical junctions, suggesting the build-up of strong compressive forces early on in their development. To study the mechanics of budding rosettes, we designed oil microdroplets stabilised by protein nanosheets displaying cadherin receptors, able to engage with receptors presented by neighbouring neuroepithelial cells, to integrate into embryoid bodies and developing organoids. The resulting artificial cells are able to sustain the formation of mature junctions with neighbouring cells and lead to the recruitment of tight junction maturation proteins such as ZO1. During early budding of neuroepithelial rosettes, artificial cells are found to be rapidly expelled from the developing organoids, further evidencing apical compressive forces. These forces are not opposed by sufficiently strong shear forces from neighbouring cells, or adhesive forces maintaining anchorage to the apical junction, to induce deformation of artificial cells.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123870"},"PeriodicalIF":12.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621099","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 : 2025-11-24DOI: 10.1016/j.biomaterials.2025.123874
Yunfeng Song , Wenting Cheng , Hailong Tian , Yichun Huang , Canhua Huang , Yongfeng Jia , Li Xu
Limited intratumoral drug accumulation and stemness-mediated immune evasion constitute fundamental barriers to effective immunotherapy in colorectal cancer (CRC). Tumor cell plasticity, fueled by metabolic reprogramming and cancer stemness, drives immunosuppressive microenvironment formation and therapeutic resistance. To overcome this, we engineered a purpurin-copper coordinated nanoplatform (TPGS/P–C@Ce6 NPs) that synergistically integrates cuproptosis induction, photodynamic therapy (PDT), and metabolic intervention. Critically, we demonstrate that surface-engineered d-α-tocopheryl polyethylene glycol succinate (TPGS) potently activates tumor cell macropinocytosis, significantly enhancing intracellular nanocarrier accumulation. Concurrently, purpurin reprograms glutamine metabolism via glutaminase inhibition, which enhances dendritic cell (DC) maturation and initiates T-cell priming. Furthermore, copper ion-driven cuproptosis synergizes with chlorin e6 (Ce6)-generated reactive oxygen species (ROS) to ablate cancer stemness, effecting robust conversion of immunologically cold tumors to T cell-inflamed hot phenotypes. Therefore, this tripartite strategy established durable immunological memory, with 100 % survival in rechallenged mice at 90 days post-treatment. This work establishes a novel metabolic-immunological co-regulation paradigm, providing a readily adaptable nanotherapeutic solution for CRC with high translational potential.
{"title":"Nano-purpurin-Cu delivery via TPGS-induced macropinocytosis enables cuproptosis/metabolic synergy to ablate cancer stemness and Boost immunotherapy in colorectal cancer","authors":"Yunfeng Song , Wenting Cheng , Hailong Tian , Yichun Huang , Canhua Huang , Yongfeng Jia , Li Xu","doi":"10.1016/j.biomaterials.2025.123874","DOIUrl":"10.1016/j.biomaterials.2025.123874","url":null,"abstract":"<div><div>Limited intratumoral drug accumulation and stemness-mediated immune evasion constitute fundamental barriers to effective immunotherapy in colorectal cancer (CRC). Tumor cell plasticity, fueled by metabolic reprogramming and cancer stemness, drives immunosuppressive microenvironment formation and therapeutic resistance. To overcome this, we engineered a purpurin-copper coordinated nanoplatform (TPGS/P–C@Ce6 NPs) that synergistically integrates cuproptosis induction, photodynamic therapy (PDT), and metabolic intervention. Critically, we demonstrate that surface-engineered <span>d</span>-α-tocopheryl polyethylene glycol succinate (TPGS) potently activates tumor cell macropinocytosis, significantly enhancing intracellular nanocarrier accumulation. Concurrently, purpurin reprograms glutamine metabolism via glutaminase inhibition, which enhances dendritic cell (DC) maturation and initiates T-cell priming. Furthermore, copper ion-driven cuproptosis synergizes with chlorin e6 (Ce6)-generated reactive oxygen species (ROS) to ablate cancer stemness, effecting robust conversion of immunologically cold tumors to T cell-inflamed hot phenotypes. Therefore, this tripartite strategy established durable immunological memory, with 100 % survival in rechallenged mice at 90 days post-treatment. This work establishes a novel metabolic-immunological co-regulation paradigm, providing a readily adaptable nanotherapeutic solution for CRC with high translational potential.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123874"},"PeriodicalIF":12.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659830","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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