X-ray-Responsive Semiconducting Polymer siRNA Nanosystems for Orthotopic Glioma Treatment via Silencing the Immunosuppressive Signal

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 (¹O₂)-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 of ¹O₂ by the SP working as the radiosensitizer under external X-ray irradiation. The generated ¹O₂ destroys the ¹O₂-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.