High-Entropy Alloy Synergized with Gene Editing for Cocktail-Sensitized Radioimmunotherapy of Lung Metastases

Radiotherapy (RT) eliminates cancer cells either through direct DNA damage induced by ionizing radiation or indirectly by generating cytotoxic reactive oxygen species (ROS) via radiolysis. However, high-dose radiation often triggers DNA repair mechanisms, undermining therapeutic efficacy and causing damage to surrounding healthy tissues. Thus, enhancing anti-tumor effects at lower doses while minimizing normal tissue damage and improving safety remains a key challenge in advancing RT technologies. To tackle these issues, we developed an RT-sensitizing platform, referred to as HAEPRC, which integrates a novel high-entropy alloy (HEA) composed of gold (Au), bismuth (Bi), platinum (Pt), silver (Ag), and palladium (Pd), a CRISPR/Cas9 gene-editing system, and tumor cell membranes (CM) for enhanced home-targeting and biocompatibility. We demonstrated that HAEPRC exhibits exceptional dose enhancement factors (DEFs), significantly boosting RT sensitization and improving RT-induced immunotherapeutic outcomes. Furthermore, the gene-editing system modulates the cell cycle, transforming RT-resistant cancer cells into RT-sensitive ones and further amplifying RT efficacy. Additionally, Pd-mediated bioorthogonal catalysis activates immune adjuvant production, enhancing immune responses and reinforcing anti-tumor immunity. Collectively, these features synergistically promote an enhanced abscopal immune effect, inhibiting lung cancer growth and metastasis, and providing a promising strategy to improve the efficacy and safety of RT.