Osteosarcoma Nanomedicine: From Resistance Reversal to Bone Reconstruction

Abstract: The clinical management of Osteosarcoma (OS) is primarily hindered by two major challenges: intractable multidrug resistance and the reconstruction of critical-sized post-surgical bone defects. Nanomedicine provides a promising paradigm to overcome these clinical limitations. Synthesizing over 100 pivotal studies published predominantly between 2021 and 2026, this review moves beyond treating OS nanotherapy and bone tissue engineering as independent fields, conceptualizing them instead as a contiguous clinical pipeline. We map the trajectory of nanoscale interventions based on OS-specific biological barriers: progressing from systemic targeted nanotherapies designed to dismantle multidrug resistance and metabolic vulnerabilities (eg, ferroptosis, cuproptosis), to the localized management of the post-resection defect. Concurrently, we highlight the evolution of skeletal reconstruction through 3D-printed, stimuli-responsive biomimetic scaffolds. These smart implants exploit the unique OS microenvironment to precisely synchronize the eradication of residual microscopic disease with osteoinductive tissue regeneration. However, unpredictable in vivo degradation and chronic toxicity remain critical translational bottlenecks. Future breakthroughs demand artificial intelligence-guided predictive design and a paradigm shift from pure cytotoxicity toward immunomodulatory architectures that facilitate host-driven tumor clearance and bone regeneration. Keywords: osteosarcoma, nanomedicine, multidrug resistance, tumor microenvironment, stimuli-responsive scaffolds