Biomaterials最新文献

{"title":"The use of a multi-metric readout screen to identify EHMT2/G9a-inhibition as a modulator of cancer-associated fibroblast activation state","authors":"Nila C. Wu ,&nbsp;Rene Quevedo ,&nbsp;Michelle Nurse ,&nbsp;Kebria Hezaveh ,&nbsp;Haijiao Liu ,&nbsp;Fumao Sun ,&nbsp;Julien Muffat ,&nbsp;Yu Sun ,&nbsp;Craig A. Simmons ,&nbsp;Tracy L. McGaha ,&nbsp;Panagiotis Prinos ,&nbsp;Cheryl H. Arrowsmith ,&nbsp;Laurie Ailles ,&nbsp;Elisa D'Arcangelo ,&nbsp;Alison P. McGuigan","doi":"10.1016/j.biomaterials.2024.122879","DOIUrl":"10.1016/j.biomaterials.2024.122879","url":null,"abstract":"<div><div>Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression, including mediating tumour cell invasion via their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM). Given that reduced CAF abundance in tumours correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in regions of tumour-stromal mixing with the goal of reducing tumour aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, we performed an image-based, phenotypic screen that enabled us to identify modulators of CAF abundance and the capacity of CAFs to induce tumour cell invasion. We identified EHMT2 (also known as G9a), an enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as a potent modulator of CAF abundance and CAF-mediated tumour cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed EHMT2 participated in driving CAFs towards a pro-invasive phenotype and mediated CAF hyperproliferation, a feature typically associated with activated fibroblasts in tumours. Our study suggests that EHMT2 regulates CAF state within the tumour microenvironment by impacting CAF activation, as well as by magnifying the pro-invasive effects of these activated CAFs on tumour cell invasion through promoting CAF hyperproliferation.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122879"},"PeriodicalIF":12.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142417470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of keratin-based fibers fabricated by interfacial polyelectrolyte complexation for suture applications","authors":"Laura Li-En Foo ,&nbsp;Muthualagu Natarajan Logeshwari ,&nbsp;Bertrand Czarny ,&nbsp;Kee Woei Ng","doi":"10.1016/j.biomaterials.2024.122878","DOIUrl":"10.1016/j.biomaterials.2024.122878","url":null,"abstract":"<div><div>Interfacial Polyelectrolyte Complexation (IPC) is a convenient way to produce composite, micro-scale fibers. In this paper, we report the successful development of novel keratin-based IPC fibers and also demonstrate the feasibility of using these fibers as sutures through a proof-of-concept <em>in vivo</em> study. Two composite fibers were produced: chitosan-keratin (CK) and keratin-keratin (KK). These fibers were evaluated for their physico-chemical, mechanical and biochemical properties. In the dry state, the CK fiber had a greater Young's modulus of about 2 GPa while the KK fiber registered a longer strain-at-break of about 100 % due to the strain-stiffening effect. Notably, the keratins were found to assemble into amyloids within the composite fibers based on Congo red staining and Wide-Angle X-Ray Scattering. Functionally, both fibers were malleable could be weaved, braided and knotted. When used as sutures to close incisional wounds in mice over 21 days, these fibers were found to elicit minimal host tissue response and were partially degraded over the duration. Interestingly, the KK fiber evoked a lower extent of immune cell response and fibrous capsule encapsulation that was comparable to commercial, non-absorbable Dafilon® sutures. This work demonstrated the possibility of producing keratin-based IPC fibers which may find practicality as medical sutures.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122878"},"PeriodicalIF":12.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405771","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}

{"title":"Revolutionizing pressure ulcer regeneration: Unleashing the potential of extracellular matrix-derived temperature-sensitive injectable antioxidant hydrogel for superior stem cell therapy","authors":"Junjie Tang,&nbsp;Penglei Zhang,&nbsp;Yadong Liu,&nbsp;Dingyu Hou,&nbsp;You Chen,&nbsp;Lili Cheng,&nbsp;Yifang Xue,&nbsp;Jie Liu","doi":"10.1016/j.biomaterials.2024.122880","DOIUrl":"10.1016/j.biomaterials.2024.122880","url":null,"abstract":"<div><div>Pressure ulcers are a common issue in elderly and medically compromised individuals, posing significant challenges in healthcare. Human umbilical cord mesenchymal stem cells (HUMSCs) offer therapeutic benefits like inflammation modulation and tissue regeneration, yet challenges in cell survival, retention, and implantation rates limit their clinical application. Hydrogels in three-dimensional (3D) stem cell culture mimic the microenvironment, improving cell survival and therapeutic efficacy. A thermosensitive injectable hydrogel (adEHG) combining gallic acid-modified hydroxybutyl chitosan (HBC-GA) with soluble extracellular matrix (adECM) has been developed to address these challenges. The hybrid hydrogel, with favorable physical and chemical properties, shields stem cells from oxidative stress and boosts their therapeutic potential by clearing ROS. The adEHG hydrogel promotes angiogenesis, cell proliferation, and collagen deposition, further enhancing inflammation modulation and wound healing through the sustained release of therapeutic factors and cells. Additionally, the adEHG@HUMSC composite induces macrophage polarization towards an M2 phenotype, which is crucial for wound inflammation inhibition and successful healing. Our research significantly propels the field of stem cell-based therapies for pressure ulcer treatment and underscores the potential of the adEHG hydrogel as a valuable tool in advancing regenerative medicine.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122880"},"PeriodicalIF":12.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386754","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}

{"title":"Glutamine synthetase accelerates re-endothelialization of vascular grafts by mitigating endothelial cell dysfunction in a rat model","authors":"Xinbo Wei ,&nbsp;Li Wang ,&nbsp;Zheng Xing ,&nbsp;Peng Chen ,&nbsp;Xi He ,&nbsp;Xiaoye Tuo ,&nbsp;Haoran Su ,&nbsp;Gang Zhou ,&nbsp;Haifeng Liu ,&nbsp;Yubo Fan","doi":"10.1016/j.biomaterials.2024.122877","DOIUrl":"10.1016/j.biomaterials.2024.122877","url":null,"abstract":"<div><div>Endothelial cell (EC) dysfunction within the aorta has long been recognized as a prominent contributor to the progression of atherosclerosis and the subsequent failure of vascular graft transplantation. However, the direct relationship between EC dysfunction and vascular remodeling remains to be investigated. In this study, we sought to address this knowledge gap by employing a strategy involving the release of glutamine synthetase (GS), which effectively activated endothelial metabolism and mitigates EC dysfunction. To achieve this, we developed GS-loaded small-diameter vascular grafts (GSVG) through the electrospinning technique, utilizing dual-component solutions consisting of photo-crosslinkable hyaluronic acid and polycaprolactone. Through an in vitro model of oxidized low-density lipoprotein-induced injury in human umbilical vein endothelial cells (HUVECs), we provided compelling evidence that the GSVG promoted the restoration of motility, angiogenic sprouting, and proliferation in dysfunctional HUVECs by enhancing cellular metabolism. Furthermore, the sequencing results indicated that these effects were mediated by miR-122-5p-related signaling pathways. Remarkably, the GSVG also exhibited regulatory capabilities in shifting vascular smooth muscle cells towards a contractile phenotype, mitigating inflammatory responses and thereby preventing vascular calcification. Finally, our data demonstrated that GS incorporation significantly enhanced re-endothelialization of vascular grafts in a ferric chloride-injured rat model. Collectively, our results offer insights into the promotion of re-endothelialization in vascular grafts by restoring dysfunctional ECs through the augmentation of cellular metabolism.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122877"},"PeriodicalIF":12.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386751","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}

{"title":"Tumor microenvironment-activated polypeptide nanoparticles for oncolytic immunotherapy","authors":"Zhihui Guo ,&nbsp;Tianze Huang ,&nbsp;Xueli Lv ,&nbsp;Renyong Yin ,&nbsp;Pengqi Wan ,&nbsp;Gao Li ,&nbsp;Peng Zhang ,&nbsp;Chunsheng Xiao ,&nbsp;Xuesi Chen","doi":"10.1016/j.biomaterials.2024.122870","DOIUrl":"10.1016/j.biomaterials.2024.122870","url":null,"abstract":"<div><div>Cationic oncolytic polypeptides have gained increasing attention owing to their ability to directly lyse cancer cells and activate potent antitumor immunity. However, the low tumor cell selectivity and inherent toxicity induced by positive charges of oncolytic polypeptides hinder their systemic application. Herein, a tumor microenvironment-responsive nanoparticle (DNP) is developed by the self-assembly of a cationic oncolytic polypeptide (PLP) with a pH-sensitive anionic polypeptide via electrostatic interactions. After the formation of DNP, the positive charges of PLP are shielded. DNPs can keep stable in physiological conditions (pH 7.4) but respond to acidic tumor microenvironment (pH 6.8) to release oncolytic PLP. As a result, DNPs evoke potent immunogenic cell death by disrupting cell membranes, damaging mitochondria and increasing intracellular levels of reactive oxygen species. <em>In vivo</em> results indicate that DNPs significantly improve the biocompatibility of PLP, and inhibit tumor growth, recurrence and metastasis by direct oncolysis and activation of antitumor immune responses. In summary, these results indicate that pH-sensitive DNPs represent a prospective strategy to improve the tumor selectivity and biosafety of cationic polymers for oncolytic immunotherapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122870"},"PeriodicalIF":12.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379688","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}

{"title":"Natural biomaterials for sustainable flexible neuromorphic devices","authors":"Yanfei Zhao ,&nbsp;Seungbeom Lee ,&nbsp;Tingyu Long ,&nbsp;Hea-Lim Park ,&nbsp;Tae-Woo Lee","doi":"10.1016/j.biomaterials.2024.122861","DOIUrl":"10.1016/j.biomaterials.2024.122861","url":null,"abstract":"<div><div>Neuromorphic electronics use neural models in hardware to emulate brain-like behavior, and provide power-efficient, extremely compact, and massively-parallel processing, so they are ideal candidates for next-generation information-processing units. However, traditional rigid neuromorphic devices are limited by their unavoidable mechanical and geometrical mismatch with human tissues or organs. At the same time, the rapid development of these electronic devices has generated a large amount of electronic waste, thereby causing severe ecological problems. Natural biomaterials have mechanical properties compatible with biological tissues, and are environmentally benign, ultra-thin, and lightweight, so use of these materials can address these limitations and be used to create next-generation sustainable flexible neuromorphic electronics. Here, we explore the advantages of natural biomaterials in simulating synaptic behavior of sustainable neuromorphic devices. We present the flexibility, biocompatibility, and biodegradability of these neuromorphic devices, and consider the potential applicability of these properties in wearable and implantable bioelectronics. Finally, we consider the challenges of device fabrication and neuromorphic system integration by natural biomaterials, then suggest future research directions.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122861"},"PeriodicalIF":12.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432211","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}

{"title":"PAR2 on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451","authors":"Divya Bhansali ,&nbsp;Nguyen H. Tu ,&nbsp;Kenji Inoue ,&nbsp;Shavonne Teng ,&nbsp;Tianyu Li ,&nbsp;Hung D. Tran ,&nbsp;Dong H. Kim ,&nbsp;Jessy Dong ,&nbsp;Chloe J. Peach ,&nbsp;Badr Sokrat ,&nbsp;Dane D. Jensen ,&nbsp;John C. Dolan ,&nbsp;Seiichi Yamano ,&nbsp;Valeria Mezzano Robinson ,&nbsp;Nigel W. Bunnett ,&nbsp;Donna G. Albertson ,&nbsp;Kam W. Leong ,&nbsp;Brian L. Schmidt","doi":"10.1016/j.biomaterials.2024.122874","DOIUrl":"10.1016/j.biomaterials.2024.122874","url":null,"abstract":"<div><div>Oral cancer is notoriously painful. Activation of protease-activated receptor 2 (PAR₂, encoded by <em>F2RL1</em>) by proteases in the cancer microenvironment is implicated in oral cancer pain. PAR₂ is a G protein-coupled receptor (GPCR) expressed on neurons and cells in the cancer microenvironment. Sustained signaling of PAR₂ from endosomes of neurons mediates sensitization and nociception. We focused on the differential contribution of PAR₂ on oral cancer cells and neurons to oral cancer pain and whether encapsulation of a PAR₂ inhibitor, AZ3451 in nanoparticles (NP) more effectively reverses PAR₂ activation. We report that <em>F2RL1</em> was overexpressed in human oral cancers and cancer cell lines. Deletion of <em>F2RL1</em> on cancer cells reduced cancer-associated mechanical allodynia. A third-generation polyamidoamine dendrimer, functionalized with cholesterol was self-assembled into NPs encapsulating AZ3451. NP encapsulated AZ3451 (PAMAM-Chol-AZ NPs) more effectively reversed activation of PAR₂ at the plasma membrane and early endosomes than free drug. The PAMAM-Chol-AZ NPs showed greater efficacy in reversing nociception than free drug, with respect to both level and duration, in three preclinical mouse models of oral cancer pain. The antinociceptive efficacy was confirmed with an operant orofacial assay. Genetic deletion of <em>F2RL1</em> on cancer cells or <em>F2rl1</em> on neurons each partially reversed mechanical cancer allodynia. The remaining nociception could be effectively reversed by PAMAM-Chol-AZ NPs. These findings suggest that PAR₂ on oral cancer cells and neurons contribute to oral cancer nociception and NPs loaded with a PAR₂ antagonist provide increased antinociception and improved oral function compared to free drug.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122874"},"PeriodicalIF":12.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441916","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}

{"title":"Enhancing CAR-T cell therapy against solid tumor by drug-free triboelectric immunotherapy","authors":"Haimei Li ,&nbsp;Zichen Wang ,&nbsp;Yulin Hu ,&nbsp;Guangqin He ,&nbsp;Liang Huang ,&nbsp;Yi Liu ,&nbsp;Zhong Lin Wang ,&nbsp;Peng Jiang","doi":"10.1016/j.biomaterials.2024.122871","DOIUrl":"10.1016/j.biomaterials.2024.122871","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cell therapy is a highly effective immunotherapy for hematological tumors, but its efficacy against most solid tumors remains challenging. Herein, a novel synergistic combination therapy of drug-free triboelectric immunotherapy and CAR-T cell therapy against solid tumor was proposed. A triboelectric nanogenerator (TENG) that can generate pulsed direct-current by coupling triboelectrification effect and electrostatic breakdown effect was fabricated. The TENG can generate up to 30 pulse direct-current peaks with peak current output ≈35 μA in a single sliding to power the triboelectric immunotherapy. The pulsed direct-current stimulation induced immunogenic cell death of tumor cells (survival rate of 35.9 %), which promoted dendritic cells maturation, accelerated the process of antigen presentation to CAR-T cells and enhanced the systemic adaptive immune response. Furthermore, triboelectric immunotherapy promoted M1-like macrophage polarization, reduced regulatory T cells differentiation and reprogrammed the tumor immunosuppressive microenvironment, which ultimately enhanced the efficacy of CAR-T cells to eradicate nearly 60 % of NALM6 solid tumor mass. Notably, considering that triboelectric immunotherapy is a safe and effective drug-free antitumor strategy, the combined therapy did not increase the burden of double-medication on patients.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122871"},"PeriodicalIF":12.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378824","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}

{"title":"LDH nanoparticles-doped cellulose nanofiber scaffolds with aligned microchannels direct high-efficiency neural regeneration and organized neural circuit remodeling through RhoA/Rock/Myosin II pathway","authors":"Xuening Pang ,&nbsp;Tongling Zhang ,&nbsp;Jiazheng Li ,&nbsp;Liqun Yu ,&nbsp;Zhibo Liu ,&nbsp;Yuchen Liu ,&nbsp;Li Li ,&nbsp;Liming Cheng ,&nbsp;Rongrong Zhu","doi":"10.1016/j.biomaterials.2024.122873","DOIUrl":"10.1016/j.biomaterials.2024.122873","url":null,"abstract":"<div><div>Spinal cord injury (SCI) triggers interconnected malignant pathological cascades culminating in structural abnormalities and composition changes of neural tissues and impairs spinal cord tissue function. Cellulose nanofibers (CNF) have considerable potential in mimicking tissue microstructure for nerve regeneration, but the effectiveness of CNF in repairing SCI remains poorly understood. In this study, we designed a Mg–Fe layered double hydroxide (LDH)-doped cellulose nanofiber (CNF) scaffold with aligned intact microchannels and homogeneously distributed pores (CNF-LDH), loaded with retinoic acid and sonic hedgehog (CNF-LDH-RS) for neuroregeneration. The aligned microchannel structure and chemical cues in the scaffold were designed further to enhance the differentiation of neural stem cells towards neurons and promote axon growth while inhibiting differentiation to astrocytes. Transplanting the scaffolds into a completely transected SCI mice model dramatically improved behavioral and electrophysiological outcomes underpinned by robust neuronal regeneration, significant axonal growth and orderly neural circuit remodeling. RNA-seq analysis revealed the pivotal roles of the RhoA/Rock/Myosin II pathway and neuroactive ligand-receptor interaction pathway in SCI repair by CNF-LDH-RS. Particularly, Myosin II emerged as a key gene for functional recovery, and its effect on negative regulation of axon growth was suppressed by the scaffolds, resulting in a distinctly oriented growth of the axons along the microchannel structure. The results indicate that CNF-LDH scaffolds rationally combined with physical and biochemical cues create promising tissue-engineered substrates to facilitate the repair of spinal cord injury.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122873"},"PeriodicalIF":12.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379687","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}

{"title":"Macrophage corpses for immunoregulation and targeted drug delivery in treatment of collagen-induced arthritis mice","authors":"Yuhuan Li ,&nbsp;Jiayin Lv ,&nbsp;Shuchen Liu ,&nbsp;Zhuoran Wang ,&nbsp;Yu Gao ,&nbsp;Zheyuan Fan ,&nbsp;Lei Huang ,&nbsp;Jing Cui ,&nbsp;Boya Zhang ,&nbsp;Xinchen Liu ,&nbsp;Zhuo Zhang ,&nbsp;Te Liu ,&nbsp;Daowei Li ,&nbsp;Modi Yang","doi":"10.1016/j.biomaterials.2024.122867","DOIUrl":"10.1016/j.biomaterials.2024.122867","url":null,"abstract":"<div><div>The role of pro-inflammatory macrophages (M1) in rheumatoid arthritis (RA) is significant, as they produce excessive cytokines. Targeting efferocytosis is a potential manner to repolarize M1 macrophages into pro-resolving M2 phenotype, which restores immune homeostasis by releasing anti-inflammatory mediators. In this study, liquid nitrogen-treated dead macrophages (DM) are employed to act as a dead cell-derived active targeted drug carrier for shikonin (SHK) and induce efferocytosis in M1 macrophages with the enhancement of SHK as an AMP-activated protein kinase (AMPK)-activator. The synergistic activation of AMPK leads to uncoupled protein 2 (UCP2) upregulation and reprograms M1 macrophages into M2 phenotypes by promoting oxidative phosphorylation. In the mouse model of collagen-induced arthritis, the intravenous administration of DM/SHK leads to a consistent transformation of M1 macrophages into the M2 phenotype within the infiltrative synovium. This transformation of macrophages results in the restoration of immune homeostasis in the synovium through an increase in the production of pro-resolving mediators. Additionally, it inhibits synovial proliferation and infiltration and provides protection against erosion of cartilage and bone. In summary, LNT-based DM serves as an active targeting drug carrier to M1 macrophages and also acts synergistically with SHK to target immunometabolism.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122867"},"PeriodicalIF":12.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374787","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}