Nanotherapeutics in osteosarcoma: Advances in miRNA nanocarriers and targeted drug delivery.

Osteosarcoma remains one of the most aggressive primary malignant bone tumor, despite all the treatment options available, there has been little progress in osteosarcoma treatment in children and young adults with metastatic or recurrent osteosarcoma. The link between dysregulated microRNAs (miRNAs) in osteosarcoma pathogenesis, metastasis, chemoresistance and immune system regulation increasingly shows that they are important drug targets for novel therapies. The clinical application of naked miRNAs is dramatically limited by the fact that they are rapidly degraded by nucleases, have a poor uptake by the cells, are poorly specific for tumors and may lead to off-target effects. Solution to these challenges is one of the innovative delivery systems based on nanocarriers that provides increased stability of miRNA, improvement of pharmacokinetics, improvement of cellular entry and a controlled release. The present review critically analyzes the ongoing developments of miRNA therapeutics for osteosarcoma focusing on the various nanocarriers such as polymeric, lipid-based, inorganic, hybrid and exosome-based nanocarriers. Rather than providing a description of every type, the review compares them based on loading capacity, biodistribution, tumor infiltration capabilities, biodegradability, their safety profiles, and potential for real-world applications. It highlights some of the main challenges of targeted drug delivery in the mineralized bone microenvironment and presents some new ideas in order to enhance the targeting of skeletal tumors with ligand-mediated and stimuli-responsive nanocarriers. The review also highlights the state-of-the-art progress in the clinical development of miRNA therapeutics, the lessons learned from those in clinical trial phases, and the major challenges to clinical application of miRNA therapeutics such as toxicity in the immune system, manufacturing scalability, batch-to-batch variability, formulation instability, regulatory issues, and cost considerations. Finally, emerging research areas are discussed, with a focus on those trends that involve advances in personalized nanomedicine (evidence-based) and strategic nanocarrier design. While there are hopeful signs of miRNA nano therapy's potential in the treatment of osteosarcoma, significant biological, technological, and regulatory hurdles remain that need to be overcome for this innovative therapy to be translated to the clinic.