Engineering TLR7/8 Agonist‐Loaded and Tumor‐Anchored Gold Nanosensitizers for Enhanced Radioimmunotherapy

Immunomodulators that can amplify the in situ vaccine effect by regulating radiation-induced immunosuppression have been proven to play a pivotal role in improving the radioimmunotherapeutic efficacy of tumors. Nevertheless, they still face challenges to be addressed for effective tumor radioimmunotherapy, such as poor tumor specificity, rapid clearance from lesions, and potential side effects. Herein, a folate receptors (FRs)-targeting and protein sulfenic acid (PSA)-reactive gold nanosystem FA-dAu-CDR is rationally designed and fabricated in which the toll-like receptor 7/8 immunoagonists are loaded through amphiphilic β-cyclodextrin (β-CD). Taking advantage of the specific covalent reaction between PSA and 1,3-cyclohexanedione (CHD) on the surface of AuNPs, this nanosystem can not only specifically target the tumor to deliver R848 agonist efficiently, but also realize high accumulation and prolonged retention of nanoparticles based on the covalent anchoring. More notably, by combining PD-L1 blockade and radiation therapy, enhanced radioimmunotherapy for both primary and distant colon tumors is achieved in living mice. Therefore, these findings offer a universal and powerful nanoplarform for effective radioimmunotherapy of malignant tumors.