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Osteoporosis is characterized by bone metabolism imbalance and chronic inflammation. Monotherapy has inherent limitations. This study integrates transcriptomic mechanism analysis and nanomaterial engineering technology to address key issues such as immune regulation imbalance and abnormal activation of the PI3K/Akt pathway revealed by the transcriptome of ovariectomized (OVX) mice, and constructs a multi-target therapeutic system targeting the immune-PI3K/Akt axis. By synthesizing bifunctional nanosheets and preparing engineered exosomes fCA-BExo, the synergistic delivery of active molecules and nanomaterials is achieved, demonstrating the ability to regulate bone metabolism and modulate the immune microenvironment in both in vivo and in vitro settings, providing a new paradigm for the treatment of this disease. Research Background
The core pathological feature of osteoporosis is the imbalance in bone metabolism and the persistent presence of chronic inflammation. The current single-target treatment approaches are unable to address multiple pathological mechanisms simultaneously, making it difficult to completely solve the treatment challenges of the disease. Therefore, it is urgent to develop multi-target synergistic treatment strategies based on mechanistic insights. Main Content
Firstly, through transcriptome analysis of OVX mice, the crucial role of immune regulation disorder and activation of the PI3K/Akt pathway in osteoclastogenesis was clearly identified; then, cobalt-aluminum layered dihydroxide nanosheets (f-CA(OH)) were synthesized. These nanosheets utilized their peroxide-like activity to eliminate reactive oxygen species (ROS) and stabilize hypoxia-inducible factor 1α (HIF-1α) to upregulate BMP2 expression. The nanosheets were co-cultured with mesenchymal stem cells (MSCs) to prepare engineered exosomes (fCA-BExo) encapsulating BMP2 and the nanomaterials. The regulatory effects of fCA-BExo on bone formation and osteoclast differentiation in vitro were systematically investigated, as well as the improvement effects on bone structure and inflammatory status of OVX mice in vivo. Research Design
Using OVX mice as the disease model, the key molecular mechanisms of the disease were first identified through transcriptomics analysis; based on the mechanism discovery, a dual-functional nanomaterial f-CA(OH) with ROS clearance and molecular regulation functions was designed; the engineered exosomes fCA-BExo were constructed through MSCs co-culture technology to achieve targeted delivery of the nanomaterial and BMP2; in vitro experiments verified the regulatory effect of fCA-BExo on osteoclast differentiation and bone formation-related signaling pathways; in vivo experiments evaluated its effects on the bone trabecular structure, inflammatory factor levels, and macrophage polarization of OVX mice, and detected the biocompatibility. Result
In vitro experiments showed that fCA-BExo could inhibit osteoclast differentiation by blocking the PI3K/Akt signaling pathway, and promote bone formation by activating the SMAD2/RUNX2 pathway. In vivo experiments demonstrated that fCA-BExo could effectively restore the bone trabecular structure of OVX mice, reduce the release of pro-inflammatory cytokines, promote the polarization of M2-type macrophages, and did not show any biological safety issues, demonstrating good biocompatibility and disease-regulating effects. Extension of Thought
This study established a collaborative research framework of "transcriptomics mechanism analysis - nano-material design - engineered exosome delivery", achieving dual effects of bone metabolism regulation and improvement of the immune microenvironment through targeting the immune-PI3K/Akt axis, providing new research ideas for the multi-mechanism collaborative treatment of osteoporosis, and offering technical references for the development of biological delivery systems combining functional nanomaterials and extracellular exosomes.
