Pub Date : 2025-12-04DOI: 10.1016/j.biomaterials.2025.123891
Dae Hee Cheon , Yoonhwa Choi , Rekha Arya , Yuna Hur , Hyeong Woon Choe , So Hee Nam , Soonsil Hyun , Akhilesh Kumar Chaurasia , Jaehoon Yu , Kyeong Kyu Kim , Yan Lee
With the growing concerns about multidrug-resistant (MDR) gram-negative bacteria, many efforts have been made to develop alternative antimicrobial agents. Exploiting outer membrane (OM)-perturbing peptides is one strategy, but their low stability and specificity have hindered clinical application. Here, two histidine-modified peptides (KLH3 and KLH4) were developed by substituting lysine residues in a novel membrane-perturbing peptide, KL-L9P, with histidine. These peptides show pH-dependent selective binding to the bacterial membrane and permeabilize the OM of gram-negative bacteria without completely disrupting it. Notably, they specifically increase the influx of non-permeable antibiotics under acidic pH. Moreover, stability studies show that KLH3 and KLH4 peptides were more stable than KL-L9P peptides, primarily due to reduced recognition by the mononuclear phagocyte system (MPS). Consequently, KLH3 and KLH4 demonstrate improved therapeutic efficacy compared to KL-L9P in mouse model of both MDR A. baumannii skin infection and E. coli NDM-1 bacteremia, while showing reduced host toxicity. These results suggest that substituting cationic residues, such as lysine or arginine, with histidine residues is a simple yet effective strategy to enhance in vivo stability and infection site specificity of OM-perturbing peptides.
{"title":"Hinged amphipathic peptides with pH-inducible positive charges: A selective battering ram against bacterial outer membrane in infection sites","authors":"Dae Hee Cheon , Yoonhwa Choi , Rekha Arya , Yuna Hur , Hyeong Woon Choe , So Hee Nam , Soonsil Hyun , Akhilesh Kumar Chaurasia , Jaehoon Yu , Kyeong Kyu Kim , Yan Lee","doi":"10.1016/j.biomaterials.2025.123891","DOIUrl":"10.1016/j.biomaterials.2025.123891","url":null,"abstract":"<div><div>With the growing concerns about multidrug-resistant (MDR) gram-negative bacteria, many efforts have been made to develop alternative antimicrobial agents. Exploiting outer membrane (OM)-perturbing peptides is one strategy, but their low stability and specificity have hindered clinical application. Here, two histidine-modified peptides (KLH3 and KLH4) were developed by substituting lysine residues in a novel membrane-perturbing peptide, KL-L9P, with histidine. These peptides show pH-dependent selective binding to the bacterial membrane and permeabilize the OM of gram-negative bacteria without completely disrupting it. Notably, they specifically increase the influx of non-permeable antibiotics under acidic pH. Moreover, stability studies show that KLH3 and KLH4 peptides were more stable than KL-L9P peptides, primarily due to reduced recognition by the mononuclear phagocyte system (MPS). Consequently, KLH3 and KLH4 demonstrate improved therapeutic efficacy compared to KL-L9P in mouse model of both MDR <em>A. baumannii</em> skin infection and <em>E. coli</em> NDM-1 bacteremia, while showing reduced host toxicity. These results suggest that substituting cationic residues, such as lysine or arginine, with histidine residues is a simple yet effective strategy to enhance <em>in vivo</em> stability and infection site specificity of OM-perturbing peptides.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123891"},"PeriodicalIF":12.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690289","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 : 2025-12-04DOI: 10.1016/j.biomaterials.2025.123892
Zhilin Jiang , Yuechun Xiao , Mengxiao Han , Xianao Hou , Hao Zhang , Tingting Wang , Wei Xing , Zhen Li
Macrophage antigen cross-presentation plays a vital role in activating CD8+ T cells for tumor immunotherapy. However, as the most abundant immune cells in glioblastoma (GBM), M2-like tumor-associated macrophages (TAMs) impede CD8+ T cell activation due to their insufficient antigen cross-presentation capability. Herein, we report a strategy of enhancing the antigen cross-presentation capability of M2-like TAMs, by precisely modulating their cysteine protease activity through the photo-controllable nanotherapeutic agent to boost the GBM immunotherapy. The therapeutic nanoprobes (i.e. NPs-RuIn-M) are rationally designed and fabricated from lanthanide nanoparticles (NPs), M2-like macrophage targeting peptide (M) coupled with ovalbumin (OVA), and Ru-caged cysteine protease inhibitor (RuIn). They can be efficiently delivered into the orthotopic GBM after temporary opening of blood-brain barrier with focused ultrasound to accurately locate M2-like TAMs by the second near-infrared-IIb (NIR IIb, 1500–1700 nm) imaging. Subsequently, under the guidance of highly sensitive NIR IIb imaging, the up-conversion emission of NPs-RuIn-M under 808 nm laser irradiation can precisely trigger the release of cysteine protease inhibitor to effectively inhibit cysteine protease activity of M2-like TAMs, thereby enhancing their antigen cross-presentation ability. The abundant M2-like TAMs in GBM can directly cross-present the OVA antigen carried by NPs-RuIn-M to effectively promote the activation and proliferation of CD8+ T cells, thereby inhibiting the growth of GBM. More importantly, in combination with anti-PD-L1 antibody and granulocyte colony-stimulating factor (G-CSF), photo-controllable NPs-RuIn-M can significantly improve the survival rate of GL261-OVA-bearing mice after irradiation with 808 nm laser. This study provides a precise and efficient photo-controllable strategy to improve the antigen cross-presentation capability of M2-like TAMs for suppressing GBM growth, which shows great potential in immunotherapy of other solid tumors with abundant M2-like TAMs.
{"title":"Targeted enhancement of antigen cross-presentation capability of M2-like tumor-associated macrophages to boost glioblastoma immunotherapy","authors":"Zhilin Jiang , Yuechun Xiao , Mengxiao Han , Xianao Hou , Hao Zhang , Tingting Wang , Wei Xing , Zhen Li","doi":"10.1016/j.biomaterials.2025.123892","DOIUrl":"10.1016/j.biomaterials.2025.123892","url":null,"abstract":"<div><div>Macrophage antigen cross-presentation plays a vital role in activating CD8<sup>+</sup> T cells for tumor immunotherapy. However, as the most abundant immune cells in glioblastoma (GBM), M2-like tumor-associated macrophages (TAMs) impede CD8<sup>+</sup> T cell activation due to their insufficient antigen cross-presentation capability. Herein, we report a strategy of enhancing the antigen cross-presentation capability of M2-like TAMs, by precisely modulating their cysteine protease activity through the photo-controllable nanotherapeutic agent to boost the GBM immunotherapy. The therapeutic nanoprobes (<em>i.e.</em> NPs-RuIn-M) are rationally designed and fabricated from lanthanide nanoparticles (NPs), M2-like macrophage targeting peptide (M) coupled with ovalbumin (OVA), and Ru-caged cysteine protease inhibitor (RuIn). They can be efficiently delivered into the orthotopic GBM after temporary opening of blood-brain barrier with focused ultrasound to accurately locate M2-like TAMs by the second near-infrared-IIb (NIR IIb, 1500–1700 nm) imaging. Subsequently, under the guidance of highly sensitive NIR IIb imaging, the up-conversion emission of NPs-RuIn-M under 808 nm laser irradiation can precisely trigger the release of cysteine protease inhibitor to effectively inhibit cysteine protease activity of M2-like TAMs, thereby enhancing their antigen cross-presentation ability. The abundant M2-like TAMs in GBM can directly cross-present the OVA antigen carried by NPs-RuIn-M to effectively promote the activation and proliferation of CD8<sup>+</sup> T cells, thereby inhibiting the growth of GBM. More importantly, in combination with anti-PD-L1 antibody and granulocyte colony-stimulating factor (G-CSF), photo-controllable NPs-RuIn-M can significantly improve the survival rate of GL261-OVA-bearing mice after irradiation with 808 nm laser. This study provides a precise and efficient photo-controllable strategy to improve the antigen cross-presentation capability of M2-like TAMs for suppressing GBM growth, which shows great potential in immunotherapy of other solid tumors with abundant M2-like TAMs.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123892"},"PeriodicalIF":12.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719902","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 : 2025-12-03DOI: 10.1016/j.biomaterials.2025.123888
Yechen Huang , Li Wang , Jie Wu , Xiaoliang Cui , Yuqi Yang , Zifan Pei , Shumin Sun , Xiaoxiao Pan , Xianmin Li , Fei Gong , Liang Cheng
Metal ion interference therapy (MIIT), which induces multiple programs of cell death, has emerged as a promising approach for combatting cancer. However, the efficient delivery of multiple metal ions and ion resistance by cellular metabolism present challenges, thereby impeding its progress. Herein, a novel MIIT initiator, layered double hydroxides composite, disulfiram (DSF)-loaded ZnCuAl-LDH, was constructed to efficiently co-deliver multiple metal ions and enhance the retention ability of metal ions within the cells. In an acidic environment, the ZCA-LDH@DSF initiator enabled pH-responsive release of Zn2+/Cu2+ and the DSF drug. On the one hand, Cu2+ and DSF in situ combined to form highly toxic CuET, inducing DNA damage and cell apoptosis. On the other hand, intracellular Cu2+ overload disrupted tricarboxylic acid cycle (TCA), leading to significant cuproptosis. Concurrently, intracellular Zn2+ inhibited the expression of the copper transport proteins ATP7A and ATP7B, reducing Cu2+ efflux and promoting intracellular Cu2+ accumulation, thereby further amplifying cuproptosis. Moreover, intracellular Zn2+ also induced pyroptosis via the caspase-1/gasdermin D (GSDMD)-dependent pathway, synergizing with CuET-induced cell apoptosis and cuproptosis to significantly enhance immunogenic cell death (ICD), which is favorable for MIIT in tumors. Therefore, ZCA-LDH@DSF demonstrated a remarkable ability to induce MIIT, thereby triggering multiple programs of cell death and inhibiting tumor growth and metastasis. Overall, the good biological safety and application prospect of ZCA-LDH@DSF initiator provide a new treatment model for combating tumor.
金属离子干扰疗法（MIIT）诱导多种细胞死亡程序，已成为对抗癌症的一种有前途的方法。然而，多种金属离子的高效传递和细胞代谢对离子的抗性存在挑战，从而阻碍了其进展。本文构建了一种新型的MIIT引发剂，层状双氢氧化物复合材料，双硫（DSF）负载的ZnCuAl-LDH，可以有效地共递送多种金属离子，并增强金属离子在细胞内的保留能力。在酸性环境下，ZCA-LDH@DSF引发剂使Zn2+/Cu2+和DSF药物的ph响应释放。一方面，Cu2+与DSF原位结合形成高毒性CuET，诱导DNA损伤和细胞凋亡。另一方面，细胞内Cu2+超载破坏了三羧酸循环（TCA），导致显著的铜还原。同时，细胞内Zn2+抑制了铜转运蛋白ATP7A和ATP7B的表达，减少了Cu2+的外排，促进了细胞内Cu2+的积累，从而进一步放大了铜还原。此外，细胞内Zn2+还通过caspase-1/gasdermin D （GSDMD）依赖性途径诱导细胞焦亡，与cuet诱导的细胞凋亡和cuprotosis协同作用，显著增强免疫原性细胞死亡（ICD），这有利于肿瘤的MIIT。因此，ZCA-LDH@DSF表现出显著的诱导MIIT的能力，从而触发多种细胞死亡程序，抑制肿瘤生长和转移。总之，ZCA-LDH@DSF引发剂良好的生物安全性和应用前景为抗肿瘤提供了一种新的治疗模式。
{"title":"A powerful agonist for metal ion interference therapy: Multiple programs of cell death to amplify tumor metalloimmunotherapy","authors":"Yechen Huang , Li Wang , Jie Wu , Xiaoliang Cui , Yuqi Yang , Zifan Pei , Shumin Sun , Xiaoxiao Pan , Xianmin Li , Fei Gong , Liang Cheng","doi":"10.1016/j.biomaterials.2025.123888","DOIUrl":"10.1016/j.biomaterials.2025.123888","url":null,"abstract":"<div><div>Metal ion interference therapy (MIIT), which induces multiple programs of cell death, has emerged as a promising approach for combatting cancer. However, the efficient delivery of multiple metal ions and ion resistance by cellular metabolism present challenges, thereby impeding its progress. Herein, a novel MIIT initiator, layered double hydroxides composite, disulfiram (DSF)-loaded ZnCuAl-LDH, was constructed to efficiently co-deliver multiple metal ions and enhance the retention ability of metal ions within the cells. In an acidic environment, the ZCA-LDH@DSF initiator enabled pH-responsive release of Zn<sup>2+</sup>/Cu<sup>2+</sup> and the DSF drug. On the one hand, Cu<sup>2+</sup> and DSF <em>in situ</em> combined to form highly toxic CuET, inducing DNA damage and cell apoptosis. On the other hand, intracellular Cu<sup>2+</sup> overload disrupted tricarboxylic acid cycle (TCA), leading to significant cuproptosis. Concurrently, intracellular Zn<sup>2+</sup> inhibited the expression of the copper transport proteins ATP7A and ATP7B, reducing Cu<sup>2+</sup> efflux and promoting intracellular Cu<sup>2+</sup> accumulation, thereby further amplifying cuproptosis. Moreover, intracellular Zn<sup>2+</sup> also induced pyroptosis via the caspase-1/gasdermin D (GSDMD)-dependent pathway, synergizing with CuET-induced cell apoptosis and cuproptosis to significantly enhance immunogenic cell death (ICD), which is favorable for MIIT in tumors. Therefore, ZCA-LDH@DSF demonstrated a remarkable ability to induce MIIT, thereby triggering multiple programs of cell death and inhibiting tumor growth and metastasis. Overall, the good biological safety and application prospect of ZCA-LDH@DSF initiator provide a new treatment model for combating tumor.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123888"},"PeriodicalIF":12.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712981","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 : 2025-12-02DOI: 10.1016/j.biomaterials.2025.123887
Huajun Wu , Xiaodong He , Liang Wu , Zhicheng Zhang , Gnanasekar Sathishkumar , Fangjing Mo , Kai Zhang , Yunlong Yu , Mahshid Kharaziha , En-Tang Kang , Zhisong Lu , Liqun Xu
Excessive wound exudate is a key factor that exacerbates wound condition, and conventional treatments typically involve its physical removal. However, the components of exudate, such as enzymes, and salts, present valuable resources that can be utilized for therapeutic purposes. To harness the potential of wound exudate, this study developed a novel exudate-responsive electrotherapy system by integrating salt-responsive polymer coatings with a yarn-based battery. Specifically, zwitterionic polymers (PVBIPS) were grafted onto the cotton yarn, which was then embedded with the antibacterial drug carvacrol. The modified yarn was further woven with anode and cathode materials to create a self-powered electric fabric dressing. The salt ions in the wound exudate triggered the dissociation of PVBIPS, enhancing the dressing's moisture retention and enabling the release of carvacrol. Furthermore, Mg(OH)2 generated during the discharge of the yarn-based battery synergistically enhanced the antibacterial effects of carvacrol. The electric field generated by the dressing promoted macrophage polarization, guided fibroblast migration and proliferation, and accelerating tissue regeneration. In both rat and porcine wound models, this electric fabric dressing significantly enhanced healing outcomes. This electric fabric dressing not only effectively utilizes wound exudate to support therapeutic functions, but also offers an alternative approach to developing multifunctional wound care systems.
{"title":"Salt-triggered electroactive dressing with controlled drug release for enhanced healing of exudative wounds","authors":"Huajun Wu , Xiaodong He , Liang Wu , Zhicheng Zhang , Gnanasekar Sathishkumar , Fangjing Mo , Kai Zhang , Yunlong Yu , Mahshid Kharaziha , En-Tang Kang , Zhisong Lu , Liqun Xu","doi":"10.1016/j.biomaterials.2025.123887","DOIUrl":"10.1016/j.biomaterials.2025.123887","url":null,"abstract":"<div><div>Excessive wound exudate is a key factor that exacerbates wound condition, and conventional treatments typically involve its physical removal. However, the components of exudate, such as enzymes, and salts, present valuable resources that can be utilized for therapeutic purposes. To harness the potential of wound exudate, this study developed a novel exudate-responsive electrotherapy system by integrating salt-responsive polymer coatings with a yarn-based battery. Specifically, zwitterionic polymers (PVBIPS) were grafted onto the cotton yarn, which was then embedded with the antibacterial drug carvacrol. The modified yarn was further woven with anode and cathode materials to create a self-powered electric fabric dressing. The salt ions in the wound exudate triggered the dissociation of PVBIPS, enhancing the dressing's moisture retention and enabling the release of carvacrol. Furthermore, Mg(OH)<sub>2</sub> generated during the discharge of the yarn-based battery synergistically enhanced the antibacterial effects of carvacrol. The electric field generated by the dressing promoted macrophage polarization, guided fibroblast migration and proliferation, and accelerating tissue regeneration. In both rat and porcine wound models, this electric fabric dressing significantly enhanced healing outcomes. This electric fabric dressing not only effectively utilizes wound exudate to support therapeutic functions, but also offers an alternative approach to developing multifunctional wound care systems.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123887"},"PeriodicalIF":12.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690288","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 : 2025-12-02DOI: 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 : 2025-11-30DOI: 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}
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