Aptamer-Functionalized Nanocarriers for Bone and Joint Diseases: Engineering Design Rules and Translational Roadmap

The escalating burden of musculoskeletal disorders, such as osteoarthritis, osteoporosis, inflammatory arthritis, bone tumors, and skeletal infections, necessitates precisely targeted therapeutics beyond conventional interventions. Nucleic acid aptamers are a next-generation ligand class distinguished by their high affinity, target specificity, low immunogenicity, and programable chemical properties. Their incorporation into nanoparticles, DNA nanostructures, hydrogels, microneedles, exosomes, and implant coatings is reshaping the therapeutic landscape of bone and joint diseases. This review synthesizes preclinical evidence from in vivo and ex vivo models, highlighting aptamer-functionalized carriers for targeting bone resorption, cartilage damage, synovial inflammation, bacterial infections, and skeletal malignancies. A classification framework based on aptamer target types, including cellular, extracellular matrix, signaling pathway, and pathogen-specific ligands, is mapped to appropriate nanocarriers and delivery routes. Key engineering parameters, including dissociation constant, ligand density, multivalency, linker design, particle size, and surface charge, are critical determinants of biodistribution, tissue penetration, and target specificity. Bone-to-reticuloendothelial system ratio and joint tissue retention metrics were proposed to guide rational design. Safety profiles, immunogenicity, and manufacturing feasibility were integrated into a translational roadmap. Standardized reporting protocols and priority indications, including intraarticular delivery in arthritis, bone defect regeneration, and targeted delivery in bone malignancies, have been identified to facilitate clinical translation.