Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released by cells, can be efficiently engineered via inverse electron demand Diels-Alder (iEDDA)-mediated conjugation to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands on the EV surface conferred substantial enhancements in signaling efficacy, particularly for tumor necrosis factor receptor superfamily (TNFRSF) agonists, where the EV surface display served as an alternative FcγR-independent approach to induce ligand multimerization and efficient receptor crosslinking. EVs displaying a complementary combination of immunotherapeutic ligands were able to shift the tumor immune milieu toward an anti-tumorigenic phenotype and significantly suppress tumor burden and increase survival in multiple models of metastatic cancer to a greater extent than an equivalent dose of free ligands. In summary, we present an EV-based delivery platform for cancer immunotherapeutic ligands that facilitates superior anti-tumor responses at significantly lower doses with fewer side effects than is possible with conventional delivery approaches.

中文翻译：

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细胞外囊泡表面显示增强了癌症免疫疗法的治疗效果和安全性


免疫疗法已成为癌症治疗的支柱，但其疗效受到免疫相关不良事件风险的限制。在这项研究中，我们提出了一种基于纳米颗粒的递送系统，该系统可增强免疫调节配体的治疗效果，同时限制全身毒性。我们证明细胞外囊泡 （EV），即细胞释放的脂质双层封闭颗粒，可以通过逆电子需求 Diels-Alder （iEDDA） 介导的偶联有效地设计，以在其表面显示多个免疫调节配体。在 EV 表面显示免疫调节配体可显著提高信号传导疗效，特别是对于肿瘤坏死因子受体超家族 （TNFRSF） 激动剂，其中 EV 表面显示作为诱导配体多聚化和有效受体交联的替代 FcγR 非依赖性方法。显示免疫治疗配体互补组合的 EV 能够将肿瘤免疫环境转变为抗肿瘤表型，并显着抑制肿瘤负荷，并在比同等剂量的游离配体更大程度上提高多种转移性癌症模型的生存率。总之，我们提出了一种基于 EV 的癌症免疫治疗配体递送平台，与传统递送方法相比，该平台以显着较低的剂量和更少的副作用促进卓越的抗肿瘤反应。