Homologous and Mitochondrial Targeting Synergistic Induction of Apoptosis and Ferroptosis Enhanced PDT Performance Against Osteosarcoma HOS

Abstract

Background: There have been no prominent advancements in osteosarcoma (OS) treatment in the past 20 years. Although photodynamic therapy (PDT) is an emerging technique for cancer therapy, its lack of targeting in OS treatment severely limits its applications.Methods: In this study, we constructed a potential theranostic nanoplatform by using (poly (ethylene glycol) polylactic-co-Glycolic acid (PEG-PLGA) nanoparticles (NPs) wrapping IR780 into the core (PEG-PLGA-IR780 NPs), which was further camouflaged with human OS cell membranes from the HOS cell line (MH-PEG-PLGA-IR780 NPs) to show homologous and mitochondrial targeting capacities. In addition, the potential underlying anticancer mechanisms of MH-PEG-PLGA-IR780 NPs-mediated PDT was investigated.Results: We demonstrated that the MH-PEG-PLGA-IR780 NPs had excellent tumor/mitochondrial targeting with the help of homologous targeting to HOS cell line. Moreover, the excellent photoacoustic (PA)/fluorescence (FL) imaging ability of MH-PEG-PLGA-IR780 NPs laid a foundation for further applications. Under near-infrared (NIR) irradiation, we demonstrated that dual-targeting NPs-mediated PDT could significantly induce HOS cell apoptosis and ferroptosis, and further explored apoptosis was triggered by cytochrome c-activated mitochondrial apoptosis (endogenous apoptosis), and the specific molecular mechanisms of ferroptosis is the activation of NCOA4-mediated ferritinophagy and the passivation of GPX4 in vitro, synergistically leading to the excessive accumulation of ROS. In addition, MH-PEG-PLGA-IR780 NPs-induced PDT also showed an obvious inhibitory effect on tumor growth in vivo. Conclusion: These results suggest the dual-targeting-based theranostic nanoplatform provides an effective method to improve PDT performance in OS and paves a new and promising way for OS therapy.