Oxygen/siRNA-carrying fluoro-nanosensitizers for radio-immunotherapy sensitization

The anti-tumor efficacy of radiotherapy (RT) is limited by the hypoxic and immunosuppressive tumor microenvironment (TME), which leads to RT resistance and failure in eradicating distant metastatic lesions. Herein, we developed a fluorinated nanosensitizer that could deliver both oxygen (O₂) and ADAR1 siRNA into tumor cells to reinforce RT by alleviating hypoxia and immunosuppression. Fluorinated poly(β-amino ester) (fPBAE) was designed to complex ADAR1 siRNA (siADAR1) via electrostatic attraction and load O₂ due to the O₂-dissolving capacity of fluoroalkyls. The formed nanocomplexes (NCs) facilitated robust cytosolic delivery into cancer cells after intratumoral injection, enabling efficient ADAR1 silencing to promote IFN-β release and enhance DC maturation and T cell infiltration. At the meantime, O₂ was released to alleviate tumoral hypoxia. As thus, NCs significantly enhanced the anti-tumor efficacy of RT and when further coupled with programmed death ligand-1 antibody, they effectively restrained the growth of both treated primary tumors and untreated distant tumors by eliciting robust systemic immune response. This study therefore reports an enlightened strategy for remodeling the immunosuppressive TME and sensitizing radio-immunotherapy. STATEMENT OF SIGNIFICANCE: The hypoxic and immunosuppressive tumor microenvironment (TME) greatly limits the anti-tumor efficacy of radiotherapy (RT). To address this critical issue, a nano-sensitizer based on fluorinated poly(β-amino ester) (fPBAE) is herein developed to mediate efficient co-delivery of oxygen (O₂) and ADAR1 siRNA into tumor cells. ADAR1 silencing promotes DC maturation and T cell infiltration to reverse immunosuppression while the released O₂ alleviates hypoxia to sensitize RT. Thus, the nano-sensitizer remarkably enhances the anti-tumor efficacy of RT and elicits robust systemic immune response to eradicate primary and distant tumors when further coupled with PD-L1 antibody. This study provides a promising approach for RT sensitization and radio-immunotherapy.