Lanmodulin-Engineered Outer Membrane Vesicles for Synergistic Targeted Radio-Immunotherapy.

Combining targeted radionuclide therapy (TRT) with immunotherapy offers a potent strategy to amplify antitumor immunity, yet the development of adaptable delivery platforms remains a challenge. Herein, we report a programmable, "plug-and-play" nanoplatform, termed TRT@LnOMVs, engineered for synergistic radio-immunotherapy. By displaying lanmodulin (LanM) on the surface of outer membrane vesicles (OMVs)-derived from attenuated Salmonella typhimurium, this platform enables the versatile and high-efficiency radiolabeling of diverse therapeutic radioisotopes under mild conditions, circumventing the limitations of conventional chelator-based methods. The platform's modularity is further demonstrated by the facile incorporation of lipid-conjugated ligands for precision targeting. In a head-to-head comparison with clinically approved 177Lu-PSMA-617 (Pluvicto), PSMA-targeted TRT@LnOMVs achieved a 90% survival rate in a prostate cancer model, far surpassing the 25% survival rate of Pluvicto. Single-cell RNA sequencing and transcriptomic analysis revealed that TRT@LnOMVs significantly remodeled the tumor immune microenvironment. This occurred through reprogramming immunosuppressive myeloid compartments (including neutrophil subsets and macrophages), expanding cytotoxic CD8+ T and NK cell infiltration, and activating innate immunity to trigger robust antitumor responses. Collectively, TRT@LnOMVs represent a versatile class of biohybrid therapeutics, offering a robust paradigm for next-generation radio-immunotherapy.