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Herein, inspired by the reprogramming of macrophages, immunoengineered porous microspheres are constructed to accelerate bone repair through the regulation of both \u201cphysical\u201d and \u201cmolecular\u201d signals. The porous structure of injectable poly (<jats:sc>l<\/jats:sc>\u2010lactic acid) (PLLA) microspheres prepared by the microfluidic technique provides a \u201cphysical signal\u201d for osteogenic differentiation. Additionally, interleukin (IL)\u20104\u2010loaded liposomes (Ls) are modified on PLLA microspheres through amide bonds to produce IL\u20104\/Ls\/PLLA microspheres, providing a \u201cmolecular signal\u201d in stimulating the differentiation of macrophages to M2 type. It is confirmed that IL\u20104\/Ls\/PLLA microspheres could induce M2\u2010macrophages polarization and potentiate osteoblast proliferation and differentiation while coculturing with macrophages and osteoblasts in vitro. Besides, IL\u20104\/Ls\/PLLA microspheres are proved to promote bone defect regeneration by inducing the conversion of M1 macrophages to M2 through dual biosignal\u2010functional regulation in both the calvaria defect and maxillary sinus defect models. Overall, the immuno\u2010reprogrammed IL\u20104\/Ls\/PLLA microspheres achieve the precise immuno\u2010reprogramming of macrophages by dual biosignal\u2010functional regulation. This immune reengineering strategy paves a way for clinical bone defect treatment.<\/jats:p>","DOI":"10.1002\/smll.202201656","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T07:43:28Z","timestamp":1649922208000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Dual Biosignal\u2010Functional Injectable Microspheres for Remodeling Osteogenic Microenvironment"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4016-753X","authenticated-orcid":false,"given":"Yang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Stomatology Zhongshan hospital Fudan University  No. 180 Fenglin road Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianrong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Stomatology Zhongshan hospital Fudan University  No. 180 Fenglin road Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital, Shanghai Jiao Tong University School of Medicine  197 Ruijin 2nd Road Shanghai 200025 P. 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