Bacteria-Derived Nanobody-Decorated Nanoplatform Restores T Cell Immunity Post-Radiotherapy.

Abstract

T cell exhaustion within the tumor immune microenvironment (TIME) impairs the efficacy of radioimmunotherapy. Here, we demonstrate that X-ray radiotherapy induces arginine metabolic dysregulation and PD-L1 upregulation in the tumor microenvironment (TME), suppressing T cell metabolism and driving the expansion of PD-1⁺TIM-3⁺ exhausted T cells, thereby promoting immunosuppression. To address this, we design a biomimetic hybrid immunomodulator (arg/B^nb-L) by engineering BL-21 bacterial membranes to display PD-L1 nanobodies and fusing them with l-arginine-loaded liposomes. This nanoplatform simultaneously blocks PD-1/PD-L1 immune checkpoint signaling and restores T cell metabolic activity while promoting dendritic cell maturation. In murine tumor models, arg/B^nb-L combined with radiotherapy significantly enhances CD8⁺ T cell infiltration, reduces exhausted T cell populations, maintains cytotoxic T lymphocyte function, and inhibits tumor progression and metastasis. Our study elucidates a dual mechanism underlying radiotherapy-induced immunosuppression and offers a promising strategy to enhance radioimmunotherapy outcomes through targeted metabolic and immunologic reprogramming.