{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T15:54:12Z","timestamp":1781366052032,"version":"3.54.1"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Age-related bone diseases, such as osteoporosis and degenerative joint disorders, pose a significant global health challenge, leading to over 9 million fractures annually, which not only diminishes quality of life but also imposes a substantial socioeconomic burden on healthcare systems. A major clinical obstacle in the aging population is the significantly reduced regenerative capacity of bone, often resulting in delayed fracture healing or nonunion fractures. Mitochondria, as the central regulators of cellular energy metabolism, are essential for determining cell fate and supporting tissue regeneration. However, age-associated mitochondrial dysfunction critically impairs these processes. While transplanting healthy mitochondria is a promising therapeutic strategy, its efficacy is severely limited by poor targeting efficiency and inherent fragility of mitochondria in circulation. Developing an efficient mitochondrial transplantation for elderly fractures is of great importance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We constructed artificial cell microspheres (Fmito@ACs) containing mitochondria of fetal mouse mesenchymal stem cells and conducted systematic characterization of them. In vitro experiments evaluated the effects of Fmito@ACs on the functions of primary osteoblasts, and its role in delaying cellular senescence was analyzed through \u03b2-galactosidase staining and immunofluorescence analysis of senescence markers (P21 and \u03b3H2A.X). Its ability to restore mitochondrial function was assessed by measuring ROS, morphology, and energy metabolism. In animal experiments, labeled Fmito@ACs were tracked using IVIS Spectrum system, and their targeted accumulation at fracture sites guided by an external magnetic field was verified. The biosafety of the system was evaluated via H&amp;amp;E staining and hepatic\/renal function parameters. Bone healing was monitored via micro-CT, X-ray, and histology on days 7, 14, and 21, while related gene expression and molecular mechanisms were analyzed by qPCR and transcriptome sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fmito@ACs were successfully constructed and characterized, indicating a protective effect on mitochondria. The system ameliorated senescence in aged BMSCs, promoting osteogenesis by enhancing mitochondrial fusion and aerobic glycolysis. In an aged fracture model, Fmito@ACs showed targeted accumulation and biosafety, significantly improving healing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>As an efficient mitochondrial-targeted delivery system, Fmito@ACs fully exploits the anti-aging effects of young mitochondria, providing a new strategy and theoretical basis for the treatment of age-related fractures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1725973","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T06:28:36Z","timestamp":1767335316000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Bone-targeted mitochondrial delivery via magnetic-temperature responsive artificial cells for repairing age-related fractures"],"prefix":"10.3389","volume":"16","author":[{"given":"Shihao","family":"Nie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taoran","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuojing","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyou","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1038\/s41586-021-03795-7","article-title":"Aged skeletal stem cells generate an inflammatory degenerative niche","volume":"597","author":"Ambrosi","year":"2021","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/s41565-025-01972-7","article-title":"An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing","volume":"20","author":"Chen","year":"2025","journal-title":"Nat. Nanotechnology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/jbmr.3864","article-title":"Calcium-sensing receptors in chondrocytes and osteoblasts are required for callus maturation and fracture healing in mice","volume":"35","author":"Cheng","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1038\/nrd.2017.116","article-title":"Senescent cells: an emerging target for diseases of ageing","volume":"16","author":"Childs","year":"2017","journal-title":"Nat. Reviews Drug Discovery"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e2424529122","DOI":"10.1073\/pnas.2424529122","article-title":"Gelated microvesicle-mediated delivery of mesenchymal stem cell mitochondria for the treatment of myocardial infarction","volume":"122","author":"Chu","year":"2025","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e13112","DOI":"10.1111\/acel.13112","article-title":"Age-related changes to macrophages are detrimental to fracture healing in mice","volume":"19","author":"Clark","year":"2020","journal-title":"Aging Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3390\/diseases4040031","article-title":"Mitochondrial dysfunction in lysosomal storage disorders","volume":"4","author":"de la Mata","year":"2016","journal-title":"Dis. Basel, Switz."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1038\/jid.2015.108","article-title":"Cell autonomous and non-autonomous effects of senescent cells in the skin","volume":"135","author":"Demaria","year":"2015","journal-title":"J. Investigative Dermatology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s00418-012-1045-x","article-title":"Astrocytes shed large membrane vesicles that contain mitochondria, lipid droplets and ATP","volume":"139","author":"Falchi","year":"2013","journal-title":"Histochem. Cell Biology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e12993","DOI":"10.1111\/acel.12993","article-title":"Peroxisome proliferator-activated receptor \u03b3 coactivator 1\u03b1 regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging","volume":"18","author":"Gill","year":"2019","journal-title":"Aging Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"122163","DOI":"10.1016\/j.biomaterials.2023.122163","article-title":"Spatially patterned 3D model mimics key features of cancer metastasis to bone","volume":"299","author":"Gonz\u00e1lez D\u00edaz","year":"2023","journal-title":"Biomaterials"},{"key":"B11","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1186\/s13287-020-01704-9","article-title":"Mitochondria transfer enhances proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell and promotes bone defect healing","volume":"11","author":"Guo","year":"2020","journal-title":"Stem Cell Research and Therapy"},{"key":"B12","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/s41586-025-09176-8","article-title":"Nerve-to-cancer transfer of mitochondria during cancer metastasis","volume":"644","author":"Hoover","year":"2025","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/s41574-025-01162-4","article-title":"The role of bone in whole-body energy metabolism","volume":"21","author":"Lecka-Czernik","year":"2025","journal-title":"Nat. Reviews Endocrinol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e0312452","DOI":"10.1371\/journal.pone.0312452","article-title":"Activity of glucose-6-phosphate dehydrogenease and its correlation with inflammatory factors in diabetic retinopathy","volume":"19","author":"Liu","year":"2024","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.bioactmat.2025.01.034","article-title":"Divalent metal ions enhance bone regeneration through modulation of nervous systems and metabolic pathways","volume":"47","author":"Luo","year":"2025","journal-title":"Bioact. Materials"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1291969","DOI":"10.3389\/fbioe.2023.1291969","article-title":"Research progress of vascularization strategies of tissue-engineered bone","volume":"11","author":"Lv","year":"2023","journal-title":"Front. Bioengineering Biotechnology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"94907375","DOI":"10.26599\/nr.2025.94907375","article-title":"Mitochondria replenishment enhances senescent periodontal ligament stem cell osteogenesis and facilitates bone repair","volume":"18","author":"Nuerlan","year":"2025","journal-title":"Nano Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"10419","DOI":"10.3390\/ijms231810419","article-title":"Single-cell RNA sequencing reveals molecular features of heterogeneity in the Murine Retinal pigment epithelium","volume":"23","author":"Pandey","year":"2022","journal-title":"Int. Journal Molecular Sciences"},{"key":"B20","doi-asserted-by":"publisher","first-page":"849","DOI":"10.3390\/ijms26020849","article-title":"Comparative transcriptomic analysis reveals new insights into spawn aging in agaricus bisporus: mitochondrial dysfunction","volume":"26","author":"Shu","year":"2025","journal-title":"Int. Journal Molecular Sciences"},{"key":"B21","doi-asserted-by":"publisher","first-page":"E859","DOI":"10.1152\/ajpendo.00054.2021","article-title":"Human blood contains circulating cell-free mitochondria, but are they really functional?","volume":"320","author":"Stier","year":"2021","journal-title":"Am. Journal Physiology Endocrinol. Metabolism"},{"key":"B22","doi-asserted-by":"publisher","first-page":"106269","DOI":"10.1016\/j.nbd.2023.106269","article-title":"Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury","volume":"186","author":"van Hameren","year":"2023","journal-title":"Neurobiol. Disease"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e2007959","DOI":"10.1002\/smll.202007959","article-title":"Mitochondria encapsulation in Hydrogel-Based artificial cells as ATP producing subunits","volume":"17","author":"Westensee","year":"2021","journal-title":"Small Weinheim der Bergstrasse, Ger."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1700530","DOI":"10.1002\/advs.201700530","article-title":"Polymer functionalization of isolated mitochondria for cellular transplantation and metabolic phenotype alteration","volume":"5","author":"Wu","year":"2018","journal-title":"Adv. Science Weinheim, Baden-Wurttemberg, Ger."},{"key":"B25","doi-asserted-by":"publisher","first-page":"713187","DOI":"10.3389\/fcvm.2021.713187","article-title":"Association of direct oral anticoagulants vs. vitamin K antagonists with fractures in atrial fibrillation patients: a systematic review and meta-analysis","volume":"8","author":"Wu","year":"2021","journal-title":"Front. Cardiovascular Medicine"},{"key":"B26","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1186\/s12951-021-01173-z","article-title":"Spatiotemporal regulation of angiogenesis\/osteogenesis emulating natural bone healing Cascade for vascularized bone formation","volume":"19","author":"Zhou","year":"2021","journal-title":"J. Nanobiotechnology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1725973\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T06:28:36Z","timestamp":1767335316000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1725973\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,2]]},"references-count":26,"alternative-id":["10.3389\/fphar.2025.1725973"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1725973","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,2]]},"article-number":"1725973"}}