Transcriptomics Guided Engineering of Exosome‐Encapsulated Bifunctional Nanosheets Targeting the Immune‐PI3K/Akt Axis for Osteoporosis Therapy

Abstract Osteoporosis, characterized by imbalanced bone metabolism and chronic inflammation, remains a therapeutic challenge due to the limitations of current single‐target therapies. This study integrates transcriptomic insights with nanomaterial engineering to develop a multi‐target strategy. Transcriptomic analysis of ovariectomized (OVX) mice reveals immune dysregulation and PI3K/Akt pathway activation, driving osteoclastogenesis. To address this, cobalt‐aluminum layered double hydroxide nanosheets (f‑CA(OH)) are synthesized, which scavenge reactive oxygen species (ROS) via peroxidase‐like activity and stabilize hypoxia‐inducible factor 1α (HIF‑1α) to upregulate BMP2 expression. Co‐culturing f‑CA(OH) with mesenchymal stem cells (MSCs) generate engineered exosomes (fCA‑BExo), encapsulating BMP2 and nanomaterials. In vitro, fCA‑BExo suppress osteoclast differentiation by blocking PI3K/Akt signaling and enhance osteogenesis via SMAD2/RUNX2 activation. In vivo, fCA‑BExo restored trabecular architecture in OVX mice, reduces pro‐inflammatory cytokines, and promote M2 macrophage polarization, demonstrating biocompatibility and efficacy. This “immune‐PI3K/Akt axis” targeting strategy offers a novel paradigm for osteoporosis treatment.