Pub Date : 2026-01-28DOI: 10.1016/j.bioactmat.2026.01.016
Weiwei Yu , Xiang Li , Xufang Liu , Xinyi Hao , Wen Qin , Guoqing Qi , Gaopeng Dang , Ziyuan Tian , Shiyin Jin , Conrado Aparicio , Kaiyan Wang , Wen Niu , Lina Niu
Oral ulceration is a prevalent mucosal disorder, and its healing process is frequently hampered by poor local drug retention and inadequate mucosal adhesion. However, the underlying pathological mechanisms remain incompletely elucidated. In this study, transcriptomic sequencing revealed that ferroptosis serves as a key driver of oral ulcer progression. To address the limitations of conventional formulations in the wet and dynamic oral environment, we constructed an asymmetrically adhesive, ferroptosis-targeting, spermidine (SPD)-functionalized Janus hydrogel microneedle system (MN-HTSO-C). This system was fabricated via chemical grafting and dynamic Schiff base crosslinking, enabling targeted drug delivery into mucosal tissues. By specifically delivering SPD, this system effectively inhibited ferroptosis, reduced reactive oxygen species (ROS) accumulation, reprogrammed the local immune microenvironment, and thereby promoted angiogenesis and epithelial regeneration. Our work not only identifies a novel pathological mechanism but also proposes an integrated therapeutic strategy that combines targeted delivery, immunomodulation, and ferroptosis inhibition, providing a new direction for the treatment of oral ulcers and other ferroptosis-related mucosal diseases.
{"title":"Spermidine-functionalized Janus hydrogel microneedles inhibit ferroptosis and promote healing of oral ulcers","authors":"Weiwei Yu , Xiang Li , Xufang Liu , Xinyi Hao , Wen Qin , Guoqing Qi , Gaopeng Dang , Ziyuan Tian , Shiyin Jin , Conrado Aparicio , Kaiyan Wang , Wen Niu , Lina Niu","doi":"10.1016/j.bioactmat.2026.01.016","DOIUrl":"10.1016/j.bioactmat.2026.01.016","url":null,"abstract":"<div><div>Oral ulceration is a prevalent mucosal disorder, and its healing process is frequently hampered by poor local drug retention and inadequate mucosal adhesion. However, the underlying pathological mechanisms remain incompletely elucidated. In this study, transcriptomic sequencing revealed that ferroptosis serves as a key driver of oral ulcer progression. To address the limitations of conventional formulations in the wet and dynamic oral environment, we constructed an asymmetrically adhesive, ferroptosis-targeting, spermidine (SPD)-functionalized Janus hydrogel microneedle system (MN-HTSO-C). This system was fabricated via chemical grafting and dynamic Schiff base crosslinking, enabling targeted drug delivery into mucosal tissues. By specifically delivering SPD, this system effectively inhibited ferroptosis, reduced reactive oxygen species (ROS) accumulation, reprogrammed the local immune microenvironment, and thereby promoted angiogenesis and epithelial regeneration. Our work not only identifies a novel pathological mechanism but also proposes an integrated therapeutic strategy that combines targeted delivery, immunomodulation, and ferroptosis inhibition, providing a new direction for the treatment of oral ulcers and other ferroptosis-related mucosal diseases.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 299-319"},"PeriodicalIF":18.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074937","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 : 2026-01-25DOI: 10.1016/j.bioactmat.2026.01.029
Jiayin Fu , Meng Zhao , Jing Zhao , Shaofei Wu , Jiahui Wu , Xulin Hong , He Huang , Guosheng Fu , Shengjie Xu
Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls. It can also lead to vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation in vivo. APOE knockout (KO) increased compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition, and increased capillary ingrowth in adventitia of the regenerated aortas. Using single cell RNA sequencing (scRNA-seq), a subset of profibrotic macrophages was found to be involved in graft fibrosis. APOE KO reduced the formation of profibrotic macrophages during vascular regeneration. The interaction between APOE and low-density lipoprotein receptor related protein 1 (LRP1) partially mediated the profibrotic macrophage formation. The profibrotic macrophages promoted graft fibrosis mainly through secretion of insulin-like growth factor-1 (IGF-1) that could support fibroblast proliferation. Finally, we showed that APOE knockdown in vivo using adeno-associated virus (AAV) improved the compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition and increased capillary ingrowth in the adventitial areas of the regenerated aortas by reducing the formation of profibrotic macrophages and their secreted IGF-1. Collectively, these data indicate that APOE can promote profibrotic macrophage formation partially through LRP1, and the profibrotic macrophages mediate graft fibrosis by increasing fibroblast proliferation via IGF-1. Inhibition of APOE generation in regenerated aortas can alleviate graft fibrosis that occurs during vascular regeneration.
{"title":"Apolipoprotein E knockout attenuates vascular graft fibrosis by reducing profibrotic macrophage formation through low-density lipoprotein receptor related protein 1","authors":"Jiayin Fu , Meng Zhao , Jing Zhao , Shaofei Wu , Jiahui Wu , Xulin Hong , He Huang , Guosheng Fu , Shengjie Xu","doi":"10.1016/j.bioactmat.2026.01.029","DOIUrl":"10.1016/j.bioactmat.2026.01.029","url":null,"abstract":"<div><div>Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls. It can also lead to vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation <em>in vivo</em>. APOE knockout (KO) increased compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition, and increased capillary ingrowth in adventitia of the regenerated aortas. Using single cell RNA sequencing (scRNA-seq), a subset of profibrotic macrophages was found to be involved in graft fibrosis. APOE KO reduced the formation of profibrotic macrophages during vascular regeneration. The interaction between APOE and low-density lipoprotein receptor related protein 1 (LRP1) partially mediated the profibrotic macrophage formation. The profibrotic macrophages promoted graft fibrosis mainly through secretion of insulin-like growth factor-1 (IGF-1) that could support fibroblast proliferation. Finally, we showed that APOE knockdown <em>in vivo</em> using adeno-associated virus (AAV) improved the compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition and increased capillary ingrowth in the adventitial areas of the regenerated aortas by reducing the formation of profibrotic macrophages and their secreted IGF-1. Collectively, these data indicate that APOE can promote profibrotic macrophage formation partially through LRP1, and the profibrotic macrophages mediate graft fibrosis by increasing fibroblast proliferation via IGF-1. Inhibition of APOE generation in regenerated aortas can alleviate graft fibrosis that occurs during vascular regeneration.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 261-279"},"PeriodicalIF":18.0,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074956","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 : 2026-01-24DOI: 10.1016/j.bioactmat.2026.01.027
Tianqi Liu , Liang Chen , Xiaoyu Zhao , Min Xie , Ling Xie , Mi Wang , Zhenyuan Wang , Jiaheng Zhang
The clinical applications of natural compounds are limited by their inherent physicochemical properties. This study reports a hierarchical supramolecular engineering strategy for constructing a dual-assembly nanosystem for the treatment of skin hyperpigmentation. Using an AI-assisted computational screening model, tranexamic acid was identified as a suitable molecular partner of the hydrophobic and active, baicalin. Subsequent dual assembly processes yielded a stable hybrid nanoplatform (DHBTC) that enhanced the solubility and delivery efficiency of baicalin. Single-cell transcriptomics revealed an unexpected mechanism of "functional inhibition"; despite the depigmenting efficacy of DHBTC, the melanogenesis-related gene network in melanocytes was upregulated. This was identified as compensatory transcriptional feedback triggered by drug-induced autophagy. DHBTC functionally inhibits pigment accumulation by accelerating melanosome degradation, which elicits ineffective transcriptional activation as the cell attempts to restore homeostasis. Furthermore, the platform remodeled the cutaneous immune microenvironment toward an anti-inflammatory state. This study presents a strategy for designing drug delivery systems, from computational prediction to supramolecular assembly, and describes a therapeutic mechanism based on the modulation of post-translational and organellar homeostasis.
{"title":"An AI-assisted designed supramolecularly engineered nanoplatform reverses pigmentation by triggering an ineffective compensatory melanin production program","authors":"Tianqi Liu , Liang Chen , Xiaoyu Zhao , Min Xie , Ling Xie , Mi Wang , Zhenyuan Wang , Jiaheng Zhang","doi":"10.1016/j.bioactmat.2026.01.027","DOIUrl":"10.1016/j.bioactmat.2026.01.027","url":null,"abstract":"<div><div>The clinical applications of natural compounds are limited by their inherent physicochemical properties. This study reports a hierarchical supramolecular engineering strategy for constructing a dual-assembly nanosystem for the treatment of skin hyperpigmentation. Using an AI-assisted computational screening model, tranexamic acid was identified as a suitable molecular partner of the hydrophobic and active, baicalin. Subsequent dual assembly processes yielded a stable hybrid nanoplatform (DHBTC) that enhanced the solubility and delivery efficiency of baicalin. Single-cell transcriptomics revealed an unexpected mechanism of \"functional inhibition\"; despite the depigmenting efficacy of DHBTC, the melanogenesis-related gene network in melanocytes was upregulated. This was identified as compensatory transcriptional feedback triggered by drug-induced autophagy. DHBTC functionally inhibits pigment accumulation by accelerating melanosome degradation, which elicits ineffective transcriptional activation as the cell attempts to restore homeostasis. Furthermore, the platform remodeled the cutaneous immune microenvironment toward an anti-inflammatory state. This study presents a strategy for designing drug delivery systems, from computational prediction to supramolecular assembly, and describes a therapeutic mechanism based on the modulation of post-translational and organellar homeostasis.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 243-260"},"PeriodicalIF":18.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036673","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 : 2026-01-24DOI: 10.1016/j.bioactmat.2026.01.023
Zhuhao Wu , Jingjing Gan , Yuanjin Zhao
Ultrasound patches have demonstrated values in non-invasive diagnostics through echo reception, while their therapeutic potentials are restricted by precisely controlling ultrasound energy and integrating multi-effects. Here, we introduce a spatiotemporal acoustic meta-patch (STAMP) that generates controllable heating, mechanical, and biological effects for synergistic multifactorial wound treatment. The STAMP utilizes acoustic metamaterial composites, including reconfigurable interdigital transducers (IDTs) and acoustic impedance matching layer, to focus and transport ultrasound energy with high spatial precision and efficiency. This patch exhibits multiple therapeutic effects, such as localized heating, ultrasound-enhanced bioactive agent delivery and cell migration. Based on these beneficial effects, we show that STAMP can precisely and spatiotemporally regulate wound microenvironments by modulating temperature, inflammation, and wound closure, providing a proof-of-concept for enhanced multifactorial wound healing. We believe that the reconfigurable and multifunctional acoustic metamaterials-based patch may open new possibilities for direct ultrasound-based therapeutics.
{"title":"Spatiotemporal acoustic meta-patches for multifactorial wound treatment","authors":"Zhuhao Wu , Jingjing Gan , Yuanjin Zhao","doi":"10.1016/j.bioactmat.2026.01.023","DOIUrl":"10.1016/j.bioactmat.2026.01.023","url":null,"abstract":"<div><div>Ultrasound patches have demonstrated values in non-invasive diagnostics through echo reception, while their therapeutic potentials are restricted by precisely controlling ultrasound energy and integrating multi-effects. Here, we introduce a spatiotemporal acoustic meta-patch (STAMP) that generates controllable heating, mechanical, and biological effects for synergistic multifactorial wound treatment. The STAMP utilizes acoustic metamaterial composites, including reconfigurable interdigital transducers (IDTs) and acoustic impedance matching layer, to focus and transport ultrasound energy with high spatial precision and efficiency. This patch exhibits multiple therapeutic effects, such as localized heating, ultrasound-enhanced bioactive agent delivery and cell migration. Based on these beneficial effects, we show that STAMP can precisely and spatiotemporally regulate wound microenvironments by modulating temperature, inflammation, and wound closure, providing a proof-of-concept for enhanced multifactorial wound healing. We believe that the reconfigurable and multifunctional acoustic metamaterials-based patch may open new possibilities for direct ultrasound-based therapeutics.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 191-202"},"PeriodicalIF":18.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036678","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 : 2026-01-24DOI: 10.1016/j.bioactmat.2026.01.031
Min Xing , Shuhan Chen , Mengjiao Zhu , Yuanming Cao , Jiayin Feng , Wenhao Qian , Kuicai Ye , Xuanyong Liu , Jiajun Qiu
Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease that lacks effective treatment options. The inflammatory microenvironment caused by excessive reactive oxygen species (ROS) in TMJ-OA leads to chondrocyte apoptosis, extracellular matrix (ECM) degradation, and abnormal cartilage metabolism. Herein, we innovatively constructed a manganese-nitrogen-carbon single-atom nanozymes (Mn-NC SAzymes) - chitosan composite hydrogel system. A coordination structure of Mn-N4 was proposed based on X-ray absorption fine structure spectra. The composite hydrogel achieves an integration of atomic level catalytic design and a localized delivery system. It fully leverages the synergistic dual enzyme-like activities of the Mn - NC SAzyme and the active repair properties of chitosan, successfully overcoming the limitations of traditional materials that target only a single site. It realizes a multi-dimensional functional synergy, ranging from efficient ROS scavenging and regulation of the inflammatory microenvironment to promoting combined bone-cartilage repair. Furthermore, through in-depth analysis of molecular mechanisms, the mechanism by which it inhibits inflammation-induced chondrocyte apoptosis and ECM degradation via suppression of the MAPK signaling pathway was elucidated. Density functional theory (DFT) was also employed to uncover the catalytic reaction pathways. This systematically explained the structure-property relationship of SAzymes and the mechanism of functional reconstruction in vivo, driving the transition of TMJ-OA treatment from mere symptom relief to multi-dimensional functional reconstruction.
{"title":"Nanozyme hydrogels remodel pathological microenvironment for temporomandibular joint osteoarthritis therapy via inhibiting MAPK signal pathway","authors":"Min Xing , Shuhan Chen , Mengjiao Zhu , Yuanming Cao , Jiayin Feng , Wenhao Qian , Kuicai Ye , Xuanyong Liu , Jiajun Qiu","doi":"10.1016/j.bioactmat.2026.01.031","DOIUrl":"10.1016/j.bioactmat.2026.01.031","url":null,"abstract":"<div><div>Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease that lacks effective treatment options. The inflammatory microenvironment caused by excessive reactive oxygen species (ROS) in TMJ-OA leads to chondrocyte apoptosis, extracellular matrix (ECM) degradation, and abnormal cartilage metabolism. Herein, we innovatively constructed a manganese-nitrogen-carbon single-atom nanozymes (Mn-NC SAzymes) - chitosan composite hydrogel system. A coordination structure of Mn-N<sub>4</sub> was proposed based on X-ray absorption fine structure spectra. The composite hydrogel achieves an integration of atomic level catalytic design and a localized delivery system. It fully leverages the synergistic dual enzyme-like activities of the Mn - NC SAzyme and the active repair properties of chitosan, successfully overcoming the limitations of traditional materials that target only a single site. It realizes a multi-dimensional functional synergy, ranging from efficient ROS scavenging and regulation of the inflammatory microenvironment to promoting combined bone-cartilage repair. Furthermore, through in-depth analysis of molecular mechanisms, the mechanism by which it inhibits inflammation-induced chondrocyte apoptosis and ECM degradation via suppression of the MAPK signaling pathway was elucidated. Density functional theory (DFT) was also employed to uncover the catalytic reaction pathways. This systematically explained the structure-property relationship of SAzymes and the mechanism of functional reconstruction <em>in vivo</em>, driving the transition of TMJ-OA treatment from mere symptom relief to multi-dimensional functional reconstruction.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 216-242"},"PeriodicalIF":18.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036682","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 : 2026-01-24DOI: 10.1016/j.bioactmat.2026.01.020
Jia-Yu Liu , Geng Shen , Yi-Chen Lin , Jing Chen , Qin-Ye Chen , Mo-Jun Lin
Arterial stiffening, a major cardiovascular risk factor, is driven by aberrant mechanotransduction in vascular smooth muscle cells (VSMCs), yet the critical mechanoreceptors and underlying mechanisms remain elusive. Here, we identified Ephrin receptor A2 (EphA2) as a significantly upregulated mechanosensitive receptor in stiffened arteries from a 5/6 nephrectomy mouse model. Genetic deletion of Epha2 in VSMCs markedly attenuated arterial stiffening. Utilizing polyacrylamide gels of varying stiffness and in situ stiffening bioclick hydrogels, we demonstrated that matrix stiffening directly induces EphA2 phase separation, forming a biomolecular condensate that serves as a signaling hub to recruit and activate ERK1/2. This leads to phosphorylation of the transcription factor CREB and subsequent upregulation of the pro-remodeling nuclear receptor NR4A3. To translate this discovery, we designed a retro-reversed peptide targeting the intrinsically disordered regions (IDRs) of EphA2, which effectively disrupted phase separation and mitigated VSMCs dysfunction in vitro. Crucially, in vivo delivery of this peptide via VAPG-modified nanoparticles significantly alleviated arterial calcification and stiffening in mice. Our study establishes EphA2 phase separation as a pivotal mechanism in vascular mechanotransduction and unveils a novel EphA2-ERK1/2-NR4A3 signaling axis, thereby presenting a promising therapeutic strategy for combating arterial stiffening by targeting pathological biomolecular condensates.
{"title":"Targeting mechanosensitive EphA2 phase separation to alleviate arterial stiffening","authors":"Jia-Yu Liu , Geng Shen , Yi-Chen Lin , Jing Chen , Qin-Ye Chen , Mo-Jun Lin","doi":"10.1016/j.bioactmat.2026.01.020","DOIUrl":"10.1016/j.bioactmat.2026.01.020","url":null,"abstract":"<div><div>Arterial stiffening, a major cardiovascular risk factor, is driven by aberrant mechanotransduction in vascular smooth muscle cells (VSMCs), yet the critical mechanoreceptors and underlying mechanisms remain elusive. Here, we identified Ephrin receptor A2 (EphA2) as a significantly upregulated mechanosensitive receptor in stiffened arteries from a 5/6 nephrectomy mouse model. Genetic deletion of Epha2 in VSMCs markedly attenuated arterial stiffening. Utilizing polyacrylamide gels of varying stiffness and in situ stiffening bioclick hydrogels, we demonstrated that matrix stiffening directly induces EphA2 phase separation, forming a biomolecular condensate that serves as a signaling hub to recruit and activate ERK1/2. This leads to phosphorylation of the transcription factor CREB and subsequent upregulation of the pro-remodeling nuclear receptor NR4A3. To translate this discovery, we designed a retro-reversed peptide targeting the intrinsically disordered regions (IDRs) of EphA2, which effectively disrupted phase separation and mitigated VSMCs dysfunction in vitro. Crucially, in vivo delivery of this peptide via VAPG-modified nanoparticles significantly alleviated arterial calcification and stiffening in mice. Our study establishes EphA2 phase separation as a pivotal mechanism in vascular mechanotransduction and unveils a novel EphA2-ERK1/2-NR4A3 signaling axis, thereby presenting a promising therapeutic strategy for combating arterial stiffening by targeting pathological biomolecular condensates.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 203-215"},"PeriodicalIF":18.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036679","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 : 2026-01-22DOI: 10.1016/j.bioactmat.2026.01.013
Shizhen Geng , Yurou Zhang , Zhehao Zhang , Di Qiu , Panmiao Liu , Xueming Fan , Shiyong Song , Jinjin Shi , Jian-jun Yang
Cancer pain, a critical complication associated with advanced malignant tumors, significantly diminishes patients’ quality of life and complicates therapeutic management due to its multifactorial pathophysiology. Current clinical analgesics often face limitations such as tolerance, addiction, and dose-dependent systemic toxicity. In contrast, micro/nano drug delivery systems (MNDDs) have emerged as promising strategies for managing cancer pain, owing to their unique advantages in precise targeting, including tumor-selective and neuropathic pain pathway targeting, controlled release, and multi-modal synergistic therapeutic effects. This review comprehensively examines the pathophysiological mechanisms underlying cancer pain, critically analyzes the pharmacological constraints and clinical limitations of existing analgesic regimens, and summarizes recent advances in engineered MNDDs. Additionally, we discuss the translational potential of multifunctional MNDDs, offering a multidisciplinary perspective to advance the development of precision-engineered, toxicity-minimized analgesic interventions.
{"title":"Applications of micro/nano drug delivery systems in cancer pain management","authors":"Shizhen Geng , Yurou Zhang , Zhehao Zhang , Di Qiu , Panmiao Liu , Xueming Fan , Shiyong Song , Jinjin Shi , Jian-jun Yang","doi":"10.1016/j.bioactmat.2026.01.013","DOIUrl":"10.1016/j.bioactmat.2026.01.013","url":null,"abstract":"<div><div>Cancer pain, a critical complication associated with advanced malignant tumors, significantly diminishes patients’ quality of life and complicates therapeutic management due to its multifactorial pathophysiology. Current clinical analgesics often face limitations such as tolerance, addiction, and dose-dependent systemic toxicity. In contrast, micro/nano drug delivery systems (MNDDs) have emerged as promising strategies for managing cancer pain, owing to their unique advantages in precise targeting, including tumor-selective and neuropathic pain pathway targeting, controlled release, and multi-modal synergistic therapeutic effects. This review comprehensively examines the pathophysiological mechanisms underlying cancer pain, critically analyzes the pharmacological constraints and clinical limitations of existing analgesic regimens, and summarizes recent advances in engineered MNDDs. Additionally, we discuss the translational potential of multifunctional MNDDs, offering a multidisciplinary perspective to advance the development of precision-engineered, toxicity-minimized analgesic interventions.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 128-162"},"PeriodicalIF":18.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036676","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 : 2026-01-22DOI: 10.1016/j.bioactmat.2025.11.039
Shuang Zhang , Shunshu Deng , Kai Dai , Yang Liu , Jing Wang , Changsheng Liu
Excessive glucocorticoid (GC) administration is a major contributor to bone marrow senescence, which subsequently contributes to the development of osteonecrosis. Conventional therapeutic approaches have shown limited efficacy, largely because current interventions are typically initiated only after a definitive diagnosis of bone deterioration—by which time the disease has often progressed to an intermediate or advanced stage, thereby missing the optimal therapeutic window for effective intervention. Here, we report that a semi-synthetic sulfated chitosan (SCS) can effectively prevent the onset of GC-induced osteonecrosis by suppressing complete senescence of the bone marrow and maintaining coupling between arterial vascularization and osteogenesis. SCS attenuates the spread of GC-induced primary adipocyte senescence into secondary senescence, effectively limiting the progressive amplification of the senescence cascade. Rather than directly intervening in the prostaglandin/PPARγ/INK positive feedback loop within the senescent adipocyte lineage, SCS functions as an extracellular matrix component that activates the IGF-1/PI3K/Akt/mTOR signaling cascade. This activation reprograms the GC-induced lineage commitment bias of bone marrow leptin receptor+ (LepR+) mesenchymal stem cells (MSCs), leading to the downregulation of adipogenic differentiation and lipid biosynthesis pathways. By attenuating upstream senescence-driving cues at the source, SCS effectively suppresses the initiation and propagation of bone marrow adipocyte senescence. Thus, this highly bioactive polysaccharide halts the onset of senescence-driven osteonecrosis at an early stage, offering a promising avenue toward upstream, preventive interventions for skeletal aging and degeneration.
{"title":"Sulfated polysaccharide prevents senescent adipocyte-driven osteonecrosis by stem cell fate reprogramming","authors":"Shuang Zhang , Shunshu Deng , Kai Dai , Yang Liu , Jing Wang , Changsheng Liu","doi":"10.1016/j.bioactmat.2025.11.039","DOIUrl":"10.1016/j.bioactmat.2025.11.039","url":null,"abstract":"<div><div>Excessive glucocorticoid (GC) administration is a major contributor to bone marrow senescence, which subsequently contributes to the development of osteonecrosis. Conventional therapeutic approaches have shown limited efficacy, largely because current interventions are typically initiated only after a definitive diagnosis of bone deterioration—by which time the disease has often progressed to an intermediate or advanced stage, thereby missing the optimal therapeutic window for effective intervention. Here, we report that a semi-synthetic sulfated chitosan (SCS) can effectively prevent the onset of GC-induced osteonecrosis by suppressing complete senescence of the bone marrow and maintaining coupling between arterial vascularization and osteogenesis. SCS attenuates the spread of GC-induced primary adipocyte senescence into secondary senescence, effectively limiting the progressive amplification of the senescence cascade. Rather than directly intervening in the prostaglandin/PPARγ/INK positive feedback loop within the senescent adipocyte lineage, SCS functions as an extracellular matrix component that activates the IGF-1/PI3K/Akt/mTOR signaling cascade. This activation reprograms the GC-induced lineage commitment bias of bone marrow leptin receptor<sup>+</sup> (LepR<sup>+</sup>) mesenchymal stem cells (MSCs), leading to the downregulation of adipogenic differentiation and lipid biosynthesis pathways. By attenuating upstream senescence-driving cues at the source, SCS effectively suppresses the initiation and propagation of bone marrow adipocyte senescence. Thus, this highly bioactive polysaccharide halts the onset of senescence-driven osteonecrosis at an early stage, offering a promising avenue toward upstream, preventive interventions for skeletal aging and degeneration.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 163-190"},"PeriodicalIF":18.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036677","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 : 2026-01-21DOI: 10.1016/j.bioactmat.2026.01.017
Leyan Xuan , Tingting Lu , Yingying Hou , Yuguang Zhu , Bingbing Zhan , Jialin Wu , Kaixiang Li , Jiachu Huang , Huaibin Wang , Ziyang Liu , Wenqi Xiao , Junjie Cai , Lijie Chen , Jie Wang , Jie Guo , Shufang Wang , Chenrui An , Xiyong Yu , Wei Fu , Guosheng Tang
Cell therapy has achieved a critical breakthrough through single-cell microgel technology. This miniaturized encapsulation platform enables precise microenvironment recapitulation, efficient targeted delivery, and tunable pericellular matrix control. Nevertheless, prevailing microfluidic and surface chemical engineering methodologies confront fundamental challenges in preserving cell viability and functionality. Here, we establish a simple and bioenzymatic strategy for fabricating single-cell microgels, using microbial transglutaminase adsorption. This surfactant- and oil-free approach, without surface modification, permits universal, high-viability encapsulation of diverse cell types and biomaterials. We achieve 100 % encapsulation efficiency and robust mechanical protection. Therapeutic efficacy was assessed in myocardial infarction (MI) and pulmonary fibrosis (PF) models. In MI, microgel-encapsulated MSCs (MSC SCMs) significantly improved in vivo retention and survival, exhibiting superior tissue regeneration and cardiac function. In bleomycin-induced PF, TNF-α-loaded MSC SCMs potentiated MMP-13 secretion, achieving enhanced respiratory function and attenuated fibrotic lesions. This robust and universally applicable platform thus for advanced cell therapies, overcomes limitations in encapsulation while demonstrating potent therapeutic efficacy across disease models.
{"title":"Bioenzymatic single-cell microencapsulation for enhanced stem Cell therapy","authors":"Leyan Xuan , Tingting Lu , Yingying Hou , Yuguang Zhu , Bingbing Zhan , Jialin Wu , Kaixiang Li , Jiachu Huang , Huaibin Wang , Ziyang Liu , Wenqi Xiao , Junjie Cai , Lijie Chen , Jie Wang , Jie Guo , Shufang Wang , Chenrui An , Xiyong Yu , Wei Fu , Guosheng Tang","doi":"10.1016/j.bioactmat.2026.01.017","DOIUrl":"10.1016/j.bioactmat.2026.01.017","url":null,"abstract":"<div><div>Cell therapy has achieved a critical breakthrough through single-cell microgel technology. This miniaturized encapsulation platform enables precise microenvironment recapitulation, efficient targeted delivery, and tunable pericellular matrix control. Nevertheless, prevailing microfluidic and surface chemical engineering methodologies confront fundamental challenges in preserving cell viability and functionality. Here, we establish a simple and bioenzymatic strategy for fabricating single-cell microgels, using microbial transglutaminase adsorption. This surfactant- and oil-free approach, without surface modification, permits universal, high-viability encapsulation of diverse cell types and biomaterials. We achieve 100 % encapsulation efficiency and robust mechanical protection. Therapeutic efficacy was assessed in myocardial infarction (MI) and pulmonary fibrosis (PF) models. In MI, microgel-encapsulated MSCs (MSC SCMs) significantly improved in vivo retention and survival, exhibiting superior tissue regeneration and cardiac function. In bleomycin-induced PF, TNF-α-loaded MSC SCMs potentiated MMP-13 secretion, achieving enhanced respiratory function and attenuated fibrotic lesions. This robust and universally applicable platform thus for advanced cell therapies, overcomes limitations in encapsulation while demonstrating potent therapeutic efficacy across disease models.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 95-112"},"PeriodicalIF":18.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036674","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 : 2026-01-21DOI: 10.1016/j.bioactmat.2026.01.009
Yun Dou , Fangxue Zhang , Zhiruo Jiang , Junqiang Mao , Haoling Guo , Yubin Li , Wujia Wang , Xiangyu Meng , Qingrui Fan , Jianjun Wang , Dong Jiang
Articular cartilage has limited capacity for self-repair due to its avascular nature. Successful cartilage repair requires the harmonious integration of sufficient stem cell recruitment, an optimal local microenvironment and a sustained repair timeframe. Here, we present a biocompatible, physically crosslinked silk fibroin platform with tunable β-sheet content (5–50 %) via freeze-assembly. This platform enables flexible and precise tuning of drug release kinetics without chemical cross-linkers. This system allows controlled drug release durations ranging from 1 to 35 days, suitable for both hydrophilic (MSC affinity peptide, MAP, serving a pro-recruiting role) and hydrophobic (kartogenin, KGN, pro-differentiating role) drugs. In a rat cartilage defect model, a sustained 21-day MAP release profile was identified as optimal, achieving an unprecedented high density of MSC recruitment (∼2.34 × 104 cells/mm3) within a differentiating-friendly timeframe. Synchronized with KGN delivery, the co-delivery system further promoted robust hyaline cartilage regeneration. This outcome may be attributed to the effect of Cdh2 genes involved in cell adhesion and p38 MAPK pathways. This work provides a structurally programmable, scalable strategy to achieve coordinated, high-density MSC recruitment and timed differentiation, advancing the paradigm of precise biomaterial design for tissue repair.
{"title":"Precisely regulated physically-crosslinked carriers enable synergetic release of bioactive factors for MSC-mediated cartilage regeneration","authors":"Yun Dou , Fangxue Zhang , Zhiruo Jiang , Junqiang Mao , Haoling Guo , Yubin Li , Wujia Wang , Xiangyu Meng , Qingrui Fan , Jianjun Wang , Dong Jiang","doi":"10.1016/j.bioactmat.2026.01.009","DOIUrl":"10.1016/j.bioactmat.2026.01.009","url":null,"abstract":"<div><div>Articular cartilage has limited capacity for self-repair due to its avascular nature. Successful cartilage repair requires the harmonious integration of sufficient stem cell recruitment, an optimal local microenvironment and a sustained repair timeframe. Here, we present a biocompatible, physically crosslinked silk fibroin platform with tunable β-sheet content (5–50 %) via freeze-assembly. This platform enables flexible and precise tuning of drug release kinetics without chemical cross-linkers. This system allows controlled drug release durations ranging from 1 to 35 days, suitable for both hydrophilic (MSC affinity peptide, MAP, serving a pro-recruiting role) and hydrophobic (kartogenin, KGN, pro-differentiating role) drugs. In a rat cartilage defect model, a sustained 21-day MAP release profile was identified as optimal, achieving an unprecedented high density of MSC recruitment (∼2.34 × 10<sup>4</sup> cells/mm<sup>3</sup>) within a differentiating-friendly timeframe. Synchronized with KGN delivery, the co-delivery system further promoted robust hyaline cartilage regeneration. This outcome may be attributed to the effect of <em>Cdh2</em> genes involved in cell adhesion and p38 MAPK pathways. This work provides a structurally programmable, scalable strategy to achieve coordinated, high-density MSC recruitment and timed differentiation, advancing the paradigm of precise biomaterial design for tissue repair.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"60 ","pages":"Pages 113-127"},"PeriodicalIF":18.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036675","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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