Barriers in bone tumor treatment: the emerging role of drug delivery systems.

Bone tumors are rare and diverse neoplasms with local and systemic impacts. Current therapies like surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy have had mixed success; significant hurdles persist. Surgery may cause a series of complications and has limited applicability. Systemic chemotherapy notably has a narrow therapeutic window. Besides, the bone microenvironment is extremely complex. These aspects fuel tumor growth and hinder drug delivery. Innovations in drug delivery systems enable spatiotemporal drug control, enhancing tumor accumulation while minimizing systemic toxicity. Examples include bone-targeted nanoparticles (e.g., bisphosphonate-modified carriers), stimuli-responsive systems (pH/redox-sensitive release), and hybrid platforms (e.g., nanocarriers co-loading chemotherapeutics and immunomodulators). These strategies address tumor heterogeneity and microenvironmental barriers, demonstrating improved efficacy in preclinical models. In this review, we comprehensively summarize the most recent advancements in drug delivery systems designed for bone tumor therapy. The key approaches discussed are as follows: drug combination strategies, metal-organic frameworks and inorganic nanomaterials, specificity of bone tissue, bone-targeting strategies, organic combination of response strategies, nanocarrier-based delivery systems, and emerging technologies. Despite progress, challenges like scalability, biocompatibility, and regulatory hurdles limit clinical translation. Future directions include integrating AI for optimized drug delivery system design, developing personalized/patient-specific delivery methods, and exploring combinatorial approaches. This review synthesizes cutting-edge DDS technologies and addresses translational challenges, providing actionable insights to bridge laboratory discoveries and clinical applications.