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A smart nano-sacrificial layer on the bone surface prevents osteoporosis through acid-base neutralization regulated biocascade effects.

Osteoporosis is a global chronic disease characterized by severe bone loss and high susceptibility to fragile fracture. It is widely accepted that the origin acidified microenvironment created by the excessive osteoclasts causes the irreversible bone mineral dissolution and organic degradation during osteoclastic resorption. However, current clinically available approaches are mainly developed from the perspective of osteoclast biology rather than the critical acidified niche. Here, we developed a smart "nano-sacrificial layer" consisting of sodium bicarbonate (NaHCO3)-containing and tetracycline-functionalized nanoliposomes (NaHCO3-TNLs) that can target bone surfaces and respond to external secreted acidification from osteoclasts, preventing osteoporosis. In vitro and in vivo results prove that this nano-sacrificial layer precisely inhibits the initial acidification of osteoclasts and initiates a chemically regulated biocascade to remodel the bone microenvironment and realize bone protection: extracellular acid-base neutralization first inhibits osteoclast function and also promotes its apoptosis, in which the apoptosis derived extracellular vesicles containing RANK further consumes RANKL in serum, achieving comprehensive osteoclast inhibition. Our therapeutic strategy for osteoporosis is based on original and precise acid-base neutralization, aiming to reestablish bone homeostasis by using a smart nano-sacrificial layer that is able to induce chemically regulated biocascade effects. This study also provides a novel understanding of osteoporosis therapy in biomedicine and clinical treatments.