Osteosarcoma remains the most prevalent and aggressive primary malignant bone tumor, mainly affecting adolescents and young adults. Despite advancements in surgical techniques and chemotherapeutic regimens, patients with metastatic or recurrent disease still have a 5-year survival rate of less than 30 % [1], [2]. This underscores the urgent need for more effective and better-integrated therapeutic strategies. Conventional treatments often fail to address two major challenges at the same time: complete tumor eradication and functional bone regeneration. This problem is particularly evident in cases with large resection-induced defects and complex tumor–bone microenvironment interactions.
In recent years, composite engineering has emerged as a practical strategy to bridge these dual therapeutic needs. It combines the distinct advantages of nanoscale precision, microscale architectural guidance, and macroscale mechanical support. Using these features, advanced biomaterials can be designed to coordinate tumor suppression, immune modulation, and bone repair within a single therapeutic platform [3], [4]. These systems can not only deliver chemotherapeutics or gene-editing agents with precise timing and location, but also provide mechanical scaffolds and biochemical cues that promote osteogenesis [5], [6], [7], [8]. Moreover, the incorporation of stimuli-responsive release mechanisms and biomimetic design principles offers unprecedented versatility for overcoming limitations associated with systemic toxicity, drug resistance, and post-surgical nonunion [9], [10].
Importantly, osteosarcoma’s complex interplay with the immune and skeletal systems presents both a challenge and an opportunity. Tumor-associated immune evasion, hypoxic metabolism, and osteolytic signaling create a hostile microenvironment that resists monotherapies[8], [11], [12]. However, emerging evidence suggests that multifunctional biomaterials can actively reshape this microenvironment. They do so by promoting antitumor immunity, regulating redox and metabolic pathways, and restoring bone homeostasis [13], [14], [15], [16], [17]. These advances position composite-based strategies not merely as passive drug carriers, but as active therapeutic agents capable of coordinating integrated biological responses.
Compared with recent reviews on nanomaterials for osteosarcoma, this article offers a complementary perspective in four respects [18], [19]. First, it proposes a cross-scale composite-engineering framework that couples material scale (nano/micro/macro) with immunomodulation, bone regeneration, and precision therapy. Second, it organizes the osteosarcoma tumor-immune microenvironment into actionable axes and aligns material design levers to each axis. Third, it defines synergy criteria and an evidence-grading rubric to differentiate genuine synergy from simple additivity. Fourth, it integrates mechanical/osteogenic requirements with oncologic endpoints (including radiosensitization) into a single decision map. Together, these components establish a coherent frame to situate prior findings and to inform subsequent material design.
This review operationalizes the above framework into a concise reading guide. We specify the inclusion focus (osteosarcoma models reporting quantitative oncologic and osteogenic endpoints), outline how studies are organized by material scale and delivery modality, and clarify the grading principles used to interpret synergy. We then examine multifunctional integration, metabolic–bone coupling, and gene–mechanical interactions, and close with key translational challenges and future directions. (Graphical Abstract)