Integration of Bone-Targeted Delivery and Crosstalk Modulation of Liver-Bone Axis for Improved Osteoporosis Therapy.

Nanomedicines hold great promise for the treatment of osteoporosis, while their nonspecific accumulation in the liver typically reduces the drug delivery efficacy. Herein, we report bone-targeted liposomes encapsulated with arginine and metformin for the treatment of osteoporosis. These liposomes are functionalized with alendronate to enhance the bone-targeting capability. The delivered agents directly modulate osteoblasts, osteoclasts, and osteocytes, promoting bone formation and inhibiting bone resorption to counteract osteoporotic bone loss. In addition to targeted bone delivery, the inevitable hepatic accumulation of liposomes is strategically utilized to stimulate the hepatic secretion of lecithin-cholesterol acyltransferase (LCAT), which, in turn, promotes bone remodeling by engaging the liver-bone axis. This dual mechanism, which combines targeted bone delivery with beneficial off-target hepatic effects, synergistically enhances therapeutic outcomes. Our findings highlight a promising nanomedicine-based strategy that takes advantage of interorgan communication to optimize osteoporosis treatment.