Nanotechnology-Driven Strategies in Osteosarcoma Advances in Treatment: Immunotherapy and Drug Delivery

Wenwen Su,1 Yuanyuan Li,1 Guang Yang,2 Yangyang Zhao,1 Xinhao Zhou,1 Guangyao Liu,3 Xu Huang,4 Muhammad Farhan Sohail,5 Irshad Hussain,6 Qihui Liu,1 Fangfang Chen1 1Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China; 2Jilin Cancer Hospital, Changchun, Jilin Province, 130012, People’s Republic of China; 3Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China; 4Department of Radiology, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China; 5Riphah Institute of Pharmaceutical Sciences (RIPS), Riphah International University, Lahore Campus, Lahore, 54000, Pakistan; 6Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Punjab, 54792, PakistanCorrespondence: Qihui Liu, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China, Tel +86-0431-84995312, Email [email protected] Fangfang Chen, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China, Tel +86-0431-84995312, Email [email protected]: Osteosarcoma (OS), the most prevalent primary malignant bone tumor, exhibits highly aggressive and metastatic potential, accounting approximately 56% of all primary malignant bone malignancies. While neoadjuvant chemotherapy with surgery remains standard, challenges persist: suboptimal margins, non-specific drug biodistribution, and systemic toxicity. Nanomaterial engineering offers transformative multifunctional platforms, integrating biomimetic targeting, stimuli-responsive release, and theranostics to enhance tumor penetration and reduce off-target effects. Immunotherapy combats OS by activating antitumor immunity, reprogramming the immunosuppressive tumor microenvironment (TME), and synergizing with checkpoint inhibitors/cell therapies. Ligand-functionalized nanocarriers significantly improve chemotherapeutic bioavailability and targeting. This review systematically explores the dual role of nanoplatforms in osteosarcoma therapeutics: (1) immunotherapy via TME reprogramming and (2) precision oncology through advanced drug delivery paradigms, providing critical insights into their translational potential for overcoming current therapeutic bottlenecks and ultimately improving clinical outcomes for OS patients. Keywords: nanomaterials, osteosarcoma, tumor microenvironment, immune regulation, drug delivery