Tailoring an intravenously injectable oncolytic virus for augmenting radiotherapy

Oncolytic viruses (OVs) combined with radiotherapy (RT) show promise but are limited by challenges such as poor intravenous delivery and insufficient RT-induced DNA damage. In this study, an oncolytic adenovirus (AD) formulation, RadioOnco (AD@PSSP), is developed to improve delivery, infectivity, immune response, and RT efficacy. The multifunctional polyethylenimine (PEI)-selenium-polyethylene glycol (PEG) (PSSP) enhances intravenous delivery, shields the virus from rapid clearance, and enables targeted delivery to tumor sites after RT. The exposed PEI enhances the infectivity of AD through electrostatic interactions, thereby increasing DNA damage after RT by inhibiting the expression of DNA repair proteins, such as CHEK1 and CDK1. Furthermore, AD-PEI captures and delivers RT-induced tumor-released antigens to lymph nodes, activating robust anti-tumor immune responses. Animal model data demonstrate that RadioOnco overcomes RT resistance, targets distant metastases, and promotes long-term immunity, addressing metastasis and recurrence. In summary, this intravenously injectable OV enhances RT synergy through surface modification with multifunctional materials. • RadioOnco can release AD-PEI under the ROS produced by tumor irradiation at a dose of 2 Gy • The released AD-PEI can enhance the sensitivity to RT through the CHK1-CDK1 pathway • AD-PEI enhances post-RT immune killing by capturing antigens to the lymph nodes • Animal studies show RadioOnco combined with RT has strong clinical translational value Xu et al. develop RadioOnco (AD@PSSP), an oncolytic adenovirus formulation that enhances intravenous delivery, viral infectivity, immune response, and radiotherapy efficacy. Through PEGylation, ROS-responsive Se-Se bonds, and PEI modification, it reverses RT resistance, targets tumors, and boosts anti-tumor immunity, showing promise for overcoming metastasis and recurrence in clinical RT.