Heterogenic membrane-coated nanoparticles for targeted immunotherapy against osteosarcoma via p53-mediated ferroptosis and mTOR inhibition

Abstract

We had identified that the expression profiles of ferroptosis-related genes correlate strongly with immune status and prognostic outcomes in osteosarcoma patients. It suggested that inducing ferroptosis while enhancing the immune response in the tumor microenvironment (TME) could be a promising therapeutic strategy for osteosarcoma. We propose using imidazole ketone erastin (IKE), a specific SLC7A11 (xCT) inhibitor, to activate ferroptosis in tumor cells for in vivo treatment of osteosarcoma. To deliver IKE to the tumor site while simultaneously modulating the immune response of TME, we designed hybrid IKE-loaded nanoparticles (TBP-IKE NPs) from bacterial outer membrane vesicles (BVs) of E. coli and tumor cell membranes (TM).TBP-IKE NPs could actively target osteosarcoma cells, inducing ferroptosis via the p53/xCT/GPX4 pathway. The RNA sequencing results showed that the upregulation of p53 could activate SESN2 and DDIT4, inhibiting mTOR to affect tumor cell metabolism. While the pathogen-associated molecular patterns (PAMPs) and LPS released from BVs, along with damage-associated molecular patterns (DAMPs) induced by ferroptosis, can activated the NLRP3 pathway in immune cells, promoting inflammatory factor release and increasing the proportion of M1-like tumor-associated macrophages, mature dendritic cells and cytotoxic T lymphocytes, to produce a durable immunotherapeutic effect. Moreover, the PAMPs and DAMPs could deplete reduced glutathione (GSH) within the tumor cells, enabling a cascade amplification of ferroptosis.In subcutaneous 143B and orthotopic K7M2 osteosarcoma models, TBP-IKE NPs inhibited tumor growth and metastasis while reprogram the immune microenvironment, providing a novel strategy for osteosarcoma treatment