Application of nano-drug delivery systems in the treatment of bone diseases: Mechanisms, strategies and challenges

• Reviews the latest nano-drug delivery systems (NDDS) applications in skeletal diseases, focusing on disease-specific needs to overcome the limitations of drug treatment. • Offers a multi-dimensional practical reference for researchers, covering material selection, size regulation, modification, drug loading and release. • Constructs a systematic, practical handy book for NDDS in orthopedics, spanning basic design to clinical translation. • Outlooks multifunctional integration and Artificial Intelligence-assisted NDDS trends, guiding clinical translation breakthroughs. As a major class of diseases threatening human health and impairing quality of life, bone diseases present significant therapeutic challenges, including low drug bioavailability and inadequate targeting. Nano-drug delivery systems (NDDS) have emerged as a cutting-edge strategy, leveraging their unique advantages in enhancing local drug concentrations, enabling precise targeting, and facilitating intelligent drug release, with evolving material technologies needing systematic sorting for optimized design and application. Focusing on bone disease therapy, this review comprehensively covers the material selection of NDDS, preparation strategies, drug loading methods, and delivery mechanisms. It elaborates on the functional design strategies of NDDS tailored to address the specific needs of bone disease treatment, such as promoting bone formation, angiogenesis, neural regulation, inflammation inhibition, and anti-tumor effects. Additionally, this review analyzes the key challenges hindering the clinical translation of NDDS, while envisioning the transformative potential of intelligent design trends. Overall, this work serves not only as a systematic reference for the precise application and optimization of NDDS in bone disease therapy but also as a handy guide to help researchers organize existing research progress and support clinicians in exploring translational therapeutic strategies—effectively bridging academic research and clinical translation to serve both communities.