Neutrophil-based Trojan horse containing polymer nano-therapeutics for sono-activatable ferroptosis-immunotherapy of orthotopic glioma

The blood-brain barrier (BBB) and tumor microenvironment of glioma limit the efficacies of various therapies, and thus glioma treatment is challenging. We herein report semiconducting polymer nano-therapeutics (SPCFe/siP) that can achieve efficient delivery into orthotopic glioma sites via neutrophil-mediated BBB transport for sono-activatable ferroptosis-immunotherapy. Such SPCFe/siP contain a semiconducting polymer, programmed death-ligand 1 (PD-L1) siRNA and iron oxide (Fe3O4) nanoparticles loaded into a singlet oxygen (1O2)-cleavable nanocarrier with surface conjugation of a neutrophil targeting ligand, sialic acid. SPCFe/siP effectively bind to neutrophils via sialic acid-based targeting pathway, and neutrophils containing SPCFe/siP serve as Trojan horses to migrate across BBB for improved delivery efficacy into orthotopic glioma sites. Upon irradiation by ultrasound (US), the semiconducting polymers produce 1O2 to destroy 1O2-cleavable nanocarriers for precise on-demand releases of Fe3O4 nanoparticles and PD-L1 siRNA, in which, Fe3O4 nanoparticles induce ferroptosis and subsequent immunogenic cell death (ICD), and PD-L1 siRNA downregulated the expression of PD-L1 for tumor cells, allowing for sono-activatable ferroptosis-immunotherapy. A strong immunological effect is formed, leading to noteworthy restriction of orthotopic glioma tumor growth and improvement of mouse survival. This study provides a neutrophil-targeting nanosystem with efficient brain delivery and activatable therapeutic action for treatment of orthotopic glioma.