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.