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The traditional approach, such as bone grafting, comes with limitations, thereby making tissue engineering strategies a potential alternative. However, successful regeneration needs both osteogenesis and proper immunomodulation. Among all the immune cells, macrophages play a pivotal role in osteoimmunomodulation because of their plasticity in switching between pro-inflammatory (M1) and anti-inflammatory (M2) states. Nanostructured biomaterials can change the polarization of macrophages by altering important immune pathways such as NF-\u03baB, MAPK, PI3K-Akt, JAK-STAT, NLRP3, Notch, and HIF-1 due to their large surface area and adjustable surface chemistry. These nanomaterials have also demonstrated excellent efficacy as carriers for targeted delivery of osteoimmunomodulatory bioactive agents, such as growth factors, cytokines, metal ions, and phytochemicals. In this review, we have discussed the crosstalk between the skeletal system, nanomaterials, and the immune system. We have also discussed the various types of nanomaterials and the design strategy of nanomaterials to modulate immune responses for enhanced bone regeneration. A brief discussion about the molecular pathways involved in osteoimmunomodulation and the modulation of these pathways by nanostructured materials for bone repair is also provided. Finally, we examined how nanomaterials can be engineered as delivery platforms for the controlled release of bioactive molecules involved in immune modulation and bone regeneration.<\/jats:p>","DOI":"10.1021\/acsbiomaterials.5c01385","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T19:32:58Z","timestamp":1769110378000},"page":"703-736","source":"Crossref","is-referenced-by-count":15,"title":["Nanostructured\nBiomaterials for Osteoimmunomodulation:\nEngineering Macrophage Polarization and Immune Pathways for Bone Regeneration"],"prefix":"10.1021","volume":"12","author":[{"given":"Jiyaur","family":"Rahaman","sequence":"first","affiliation":[{"name":"SVKM\u2019s Narsee Monjee Institute of Management Studies , , , ,","place":["Shirpur, Maharashtra, India, 425405"]},{"name":"SVKM\u2019s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be University , , V.L. Mehta Road, Vile Parle (West) , , ,","place":["Mumbai, Maharashtra, India, 400056"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3011-5733","authenticated-orcid":true,"given":"Dhrubojyoti","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"SVKM\u2019s Narsee Monjee Institute of Management Studies , , , ,","place":["Shirpur, Maharashtra, India, 425405"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"2026090710071422700_cit1","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1016\/j.jconrel.2025.02.048","article-title":"Nanocomposite\nhydrogels optimize the microenvironment by exterior\/interior\ncrosstalk for reprogramming osteoporotic homeostasis in bone defect\nhealing","volume":"380","author":"Chen","year":"2025","journal-title":"J. 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