Abstract
Gliomas are the most lethal types of adult brain tumors with a devastating prognosis, but many therapies have failed to exert good therapeutic benefits because of the extremely hypoxic and immunosuppressive tumor microenvironment. To address these challenges, we herein present a semiconducting polymer (SP)-based small interfering RNA (siRNA) nanosystem with the loading of oxygen self-supplying perfluorohexane (PFH) and conjugation of siRNA via a singlet oxygen (O)-cleavable linker. The nanosystems are further camouflaged with a macrophage membrane to obtain the final RM@SPN-siRNA. RM@SPN-siRNA displays an enhanced enrichment at the orthotopic glioma site due to surface cell membrane camouflaging. PFH provides sufficient oxygen to relieve tumor hypoxia, which boosts the production ofOby the SP working as the radiosensitizer under external X-ray irradiation. The generatedOdestroys theO-cleavable linker and disrupts the membrane structure to enable in situ siRNA release at the tumor site and subsequent activatable programmed death ligand-1 (PD-L1) silencing for tumor cells. As a consequence, an immunological effect is triggered to effectively inhibit tumor growths in an orthotopic glioma mouse model. This study offers an X-ray-responsive siRNA nanosystem for precise protein silencing and treatment of deep-seated orthotopic tumors.
Overview
- The study aims to develop a semiconducting polymer-based small interfering RNA (siRNA) nanosystem to target gliomas, a type of lethal brain tumor.
- The nanosystem is designed to alleviate tumor hypoxia and improve therapeutic efficacy by incorporating oxygen self-supplying perfluorohexane (PFH) and a singlet oxygen-cleavable linker.
- The study explores the potential of this nanosystem to trigger immunological effects and inhibit tumor growth in an orthotopic glioma mouse model.
Comparative Analysis & Findings
- The RM@SPN-siRNA nanosystem displayed enhanced enrichment at the orthotopic glioma site due to surface cell membrane camouflaging and PFH-mediated oxygen supply.
- External X-ray irradiation triggered the destruction of O-cleavable linker and in situ siRNA release at the tumor site, leading to PD-L1 silencing and immunological effects.
- The nanosystem effectively inhibited tumor growth in an orthotopic glioma mouse model, offering a promising approach for precise protein silencing and treatment of deep-seated tumors.
Implications and Future Directions
- The X-ray-responsive siRNA nanosystem has potential applications in the treatment of various types of tumors, including orthotopic gliomas.
- Future studies can focus on optimizing the design of the nanosystem and exploring its combination with other therapies for improved therapeutic efficacy.
- The study's findings also highlight the importance of addressing tumor hypoxia and immunosuppression in the development of effective therapies for gliomas.