Osteosarcoma (OS) is a primary malignant bone tumor with a high propensity for metastasis, particularly in adolescents and young adults. Despite advances in cancer therapy, the current standard of care for OS has remained largely unchanged since the 1980s, resulting in suboptimal survival rates, particularly for patients with metastatic disease. The tumor microenvironment (TME) plays a critical role in promoting OS progression and metastasis, with resident tumor-associated macrophages (TAMs) emerging as key contributors to the immunosuppressive and pro-tumoral environment. Reprogramming TAMs from a pro-tumoral (M2-like) to an antitumoral (M1-like) phenotype is an attractive therapeutic strategy. In OsteoTher project, we propose a new therapeutic approach in OS, which utilizes in vitro transcribed (IVT) mRNA-based polymeric nanocarriers (NCs) to reeducate the TME and resident TAMs. These NCs will deliver mRNA encoding M1-polarizing transcription factors to shift the TAMs towards an anti-tumor phenotype. OsteoTher focuses on developing targeted polymeric NCs that are biodegradable, biocompatible, and sustainably released at the tumor site.
These NCs will actively target M2 TAMs via macrophage mannose receptor CD-206 or macrophage hyaluronan receptor CD-44, inducing TAM repolarization. Furthermore, the OsteoTher platform allows for the loading of multiple drugs, potentially enabling synergistic combination, therapy by creating NCs-loaded hydrogel scaffolds for localized delivery using 3D bioprinting and electrospinning techniques. Mouse models treated with OsteoTher will show the efficacy of mRNA-NCs and combination therapies by converting immunosuppressive macrophages into proinflammatory/OS suppressive phenotypes.
Overall, OsteoTher offers a promising avenue for OS treatment, harnessing the power of mRNA-based nanocarriers to reprogram the TME and TAMs, potentially leading to improved patient outcomes and a more effective approach to combatting this aggressivebone cancer.