Rectifying the Crosstalk between the Skeletal and Immune Systems Improves Osteoporosis Treatment by Core–Shell Nanocapsules

Contemporary osteoporosis treatment often neglects the intricate interactions among immune cells, signaling proteins, and cytokines within the osteoporotic microenvironment. Here, we developed core–shell nanocapsules composed of a cationized lactoferrin core and an alendronate polymer shell. By tuning the size of these nanocapsules and leveraging the alendronate shell, we enabled precise delivery of small interfering RNA targeting the Semaphorin 4D gene (siSema4D) to specific bone sites. This strategy integrates the antiresorptive drug alendronate with siSema4D, efficiently inhibiting osteoclast (OC) differentiation and bone resorption, while promoting osteogenesis to restore the balance between osteoblasts (OBs) and OCs. Moreover, encapsulating siSema4D within the nanocapsules helps to mitigate immunological cascades, thereby reversing the inflammatory microenvironment and restoring immune homeostasis and providing insights into the immunomodulatory effects of Sema4D in osteoporosis therapy. In both ovariectomized and senile osteoporotic mouse models, local intramuscular administration of core–shell nanocapsules effectively rectified the imbalance between the skeletal and immune systems, significantly enhancing the overall efficacy of osteoporosis treatment. Our findings underscore the therapeutic promise of addressing the multifaceted osteoporotic microenvironment through targeted interventions.