Bone-Directed Drug Delivery: From Mineral and Matrix Recognition to Cellular Regulation

Bone-targeted drug delivery aims to increase drug exposure at diseased skeletal sites while reducing unnecessary exposure in non-skeletal tissues. Bone provides two complementary targets—the mineralized extracellular matrix and the cells regulating bone remodeling. Structural targeting uses the calcium- and phosphate-rich hydroxyapatite surfaces or collagen-rich extracellular matrix as binding sites for therapeutic cargos and delivery carriers. Cellular targeting aims to regulate osteoclasts, osteoblast-lineage cells, osteocytes, and key remodeling pathways, including receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin, Wnt/sclerostin, bone morphogenetic protein, and parathyroid hormone 1 receptor signaling. Targeting ligands and delivery platforms, including bisphosphonates, acidic oligopeptides, tetracyclines, collagen-hybridizing peptides, calcium phosphate materials, nanoparticles, aptamers, nucleic acid vectors, and extracellular vesicles, have been developed to enhance skeletal localization, prolong retention, improve cellular uptake, and control cargo release. Clinical experience with anti-RANKL antibodies, sclerostin antibodies, and parathyroid hormone receptor agonists further demonstrates the therapeutic value of regulating bone-remodeling pathways. Successful translation requires more than skeletal accumulation and should establish microanatomical localization, target-cell engagement, cargo release, therapeutic efficacy, and long-term safety. Integrating structural and cellular targeting may enable more precise treatment of osteoporosis, fracture repair, bone infection, and skeletal malignancies.