Abstract Small-molecule tyrosine kinase inhibitors (TKIs) represent a potentially powerful approach to the treatment of osteosarcoma (OS). However, dose-limiting toxicity, therapeutic efficacy, and targeting specificity are significant barriers to the use of TKIs in the clinic. Notably among TKIs, ponatinib demonstrated potent anti-tumor activity; however, it received an FDA black box warning for potential side effects. We propose ponatinib-loaded biomimetic nanoparticles (NPs) to repurpose ponatinib as an efficient therapeutic option for OS. In this study, we demonstrate enhanced targeting ability and maintain potent ponatinib nano-therapeutic activity, while also reducing toxicity. In in vitro two- and three-dimensional models, we demonstrate that ponatinib-loaded biomimetic NPs maintain the efficacy of the free drug, while in vivo we show that they can improve tumor targeting, slow tumor growth, and reduce evidence of systemic toxicities. Though there is limited Pon encapsulation within NPs, this platform may improve current therapeutic approaches and reduce dosage-related side effects to achieve better clinical outcomes in OS patients. Graphical Abstract

Tyrosine kinase inhibitor-loaded biomimetic nanoparticles as a treatment for osteosarcoma