Enhancing Tumor Immunotherapy by Multivalent Anti‐PD‐L1 Nanobody Assembled via Ferritin Nanocage

Abstract Increasing immunotherapy response rate and durability can lead to significant improvements in cancer care. To address this challenge, a novel multivalent immune checkpoint therapeutic platform is constructed through site‐specific ligation of anti‐PD‐L1 nanobody (Nb) on ferritin (Ftn) nanocage. Nb‐Ftn blocks PD‐1/PD‐L1 interaction and downregulates PD‐L1 levels via endocytosis‐induced degradation. In addition, the cage structure of Ftn allows encapsulation of indocyanine green (ICG), an FDA‐approved dye. Photothermal treatment with Nb‐Ftn@ICG induces immunogenic death of tumor cells, which improves systemic immune response via maturation of dendritic cells and enhanced infiltration of T cells. Moreover, Nb‐Ftn encapsulation significantly enhances cellular uptake, tumor accumulation and retention of ICG. In vivo assays showed that this nanoplatform ablates the primary tumor, suppresses abscopal tumors and inhibits tumor metastasis, leading to a prolonged survival rate. This work presents a novel strategy for improving cancer immunotherapy using multivalent nanobody‐ferritin conjugates as immunological targeting and enhancing carriers.