Oncolytic viruses (OVs) combined with radiotherapy (RT) have shown promise in clinical trials but remain limited by unsatisfactory efficacy. Key challenges include poor intravenous delivery, insufficient RT-induced DNA damage, and suboptimal anti-tumor immune responses. Herein, we developed a novel oncolytic adenovirus (AD) formulation, RadioOnco (AD@PSSP), which incorporates multifunctional polyethyleneimine (PEI)-selenium-PEG (PSSP) to enhance intravenous delivery, viral infectivity, immune response and the efficacy of radiotherapy. The PEGylation shields the virus from rapid clearance, while the ROS-responsive Se-Se bond enables targeted delivery at tumor sites following RT. The exposed PEI enhanced infectivity of AD through electrostatic interactions, consequently augmenting DNA damage after RT via inhibiting the expression of DNA-repair proteins, such as CHEK1 and CDK1. Furthermore, AD-PEI can capture and deliver the RT-induced tumor-released antigens to lymph nodes, thereby activating robust anti-tumor immune responses. Our data from diverse animal models have shown that RadioOnco exhibits unique characteristics, including reversing RT resistance, ability for distant killing, and long-term memory retention, all of which are crucial for addressing metastasis and recurrence in clinical RT. In summary, we have devised an intravenously injectable OVs with synergistic effects in conjunction with RT, achieved through the surface modification of a multifunctional material.