Ex Vivo High-Dose Ionizing Irradiation-Conditioned Nanovesicles for Enhancing the Immune Effects of Tumor Radiotherapy

作者：Jinrong Yang, Hongmei Cao, Huan Tang, Zhuoran Yin, Paiyun Li, Jianfeng Liu, Cuihong Yang, Wenxue Zhang · 发表于：ACS Applied Materials & Interfaces · 年份：2025 · DOI：10.1021/acsami.5c10385 · 被引用次数：4 · 研究领域：Extracellular vesicles in disease、Immunotherapy and Immune Responses、Immune cells in cancer

Radiotherapy (RT) exhibits a dose-dependent duality in its impact on antitumor immunity. While high-dose irradiation induces immunogenic cell death (ICD) and enhances immune responses, conventional RT is limited by toxicity and may paradoxically promote immunosuppression via myeloid-derived suppressor cells (MDSCs) infiltration and M2 macrophage polarization. To address this challenge, we leveraged ex vivo high-dose irradiation to generate tumor-derived exosomes (cExo) enriched with immunostimulatory components. Proteomic analysis revealed that cExo were enriched with damage-associated molecular patterns (DAMPs), including high mobility group box 1 protein (HMGB1) and calreticulin (CRT), as well as major histocompatibility complex I (MHC I), thereby enhancing dendritic cells (DCs) activation and antigen cross-presentation. Building upon these findings, we developed a hybrid nanoplatform (cExo-Lip) by fusing immunogenic cExo with liposomes loaded with plasmid IL-12 (pIL-12). This design compensates for the limited immunogenicity of low-dose irradiation by delivering MHC I and DAMPs via cExo, thereby enhancing DCs maturation and cytotoxic T lymphocyte (CTLs) priming. Moreover, sustained IL-12 expression further remodels the tumor immune microenvironment by reprogramming M2 macrophages toward a tumoricidal M1 phenotype and enhancing CTLs activation, thereby synergistically amplifying RT-induced immune responses. In B16F10 melanoma mouse models, combining 6 Gy RT with pIL-12@cExo...