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In this study, we developed pH\u2010responsive ZIF\u201090 nanoparticles loaded with puerarin (PU) (ZIF\u201090@PU) for microenvironment\u2010responsive osteoporosis therapy through epigenetic modulation. Following self\u2010assembly, the nanoparticles underwent dynamic light scattering (DLS), field emission scanning electron microscopy (FE\u2010SEM), powder X\u2010ray diffraction (PXRD), Fourier\u2010transform infrared spectroscopy (FTIR), and X\u2010ray photoelectron spectroscopy (XPS); these analyses verified efficient puerarin encapsulation and pH\u2010triggered release. In cell\u2010based experiments, ZIF\u201090@PU suppressed the differentiation of bone marrow\u2010derived macrophages (BMMs) into osteoclasts while promoting osteogenic differentiation of bone marrow\u2010derived mesenchymal stem cells (BMSCs). Administration of ZIF\u201090@PU to ovariectomized (OVX) mice produced significant gains in bone mineral density, trabecular architecture, and bone strength without detectable toxicity. Mechanistically, ZIF\u201090@PU treatment was associated with increased H3K18 lactylation and reduced NFATc1 signaling, accompanied by suppression of osteoclast activation. This study introduces ZIF\u201090@PU as a novel epigenetic\u2010modulating nanomedicine for osteoporosis treatment.<\/jats:p>","DOI":"10.1002\/advs.77869","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Puerarin\u2011Loaded pH\u2011Responsive ZIF\u201190 Nanoparticles Ameliorate Osteoporosis via Enhancing H3K18 Lactylation and Suppressing Aberrant Osteoclast Activation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0957-592X","authenticated-orcid":false,"given":"Jiajia","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Orthopedic Trauma School of Medicine Shanghai Fourth People's Hospital Tongji University  Shanghai People's Republic of China"},{"name":"Department of Orthopedic Trauma Haimen People's Hospital of Jiangsu Province  Haimen People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Guangming Traditional Chinese Medicine Hospital of Pudong New Area  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Trauma School of Medicine Shanghai Fourth People's Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Trauma Haimen People's Hospital of Jiangsu Province  Haimen People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Trauma Haimen People's Hospital of Jiangsu Province  Haimen People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8904-6096","authenticated-orcid":false,"given":"Xiaojian","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Trauma Haimen People's Hospital of Jiangsu Province  Haimen People's Republic of 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