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This study integrates transcriptomic insights with nanomaterial engineering to develop a multi\u2010target strategy. Transcriptomic analysis of ovariectomized (OVX) mice reveals immune dysregulation and PI3K\/Akt pathway activation, driving osteoclastogenesis. To address this, cobalt\u2010aluminum layered double hydroxide nanosheets (f\u2011CA(OH)) are synthesized, which scavenge reactive oxygen species (ROS) via peroxidase\u2010like activity and stabilize hypoxia\u2010inducible factor 1\u03b1 (HIF\u20111\u03b1) to upregulate BMP2 expression. Co\u2010culturing f\u2011CA(OH) with mesenchymal stem cells (MSCs) generate engineered exosomes (fCA\u2011BExo), encapsulating BMP2 and nanomaterials. In vitro, fCA\u2011BExo suppress osteoclast differentiation by blocking PI3K\/Akt signaling and enhance osteogenesis via SMAD2\/RUNX2 activation. In vivo, fCA\u2011BExo restored trabecular architecture in OVX mice, reduces pro\u2010inflammatory cytokines, and promote M2 macrophage polarization, demonstrating biocompatibility and efficacy. This \u201cimmune\u2010PI3K\/Akt axis\u201d targeting strategy offers a novel paradigm for osteoporosis treatment.<\/jats:p>","DOI":"10.1002\/advs.202511327","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T05:32:18Z","timestamp":1759210338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptomics Guided Engineering of Exosome\u2010Encapsulated Bifunctional Nanosheets Targeting the Immune\u2010PI3K\/Akt Axis for Osteoporosis Therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Rongze","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Affiliated Hospital of Xuzhou Medical University  Jiangsu 221004 China"},{"name":"Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University  Jiangsu 221004 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