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

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.