Migara Kavishka Jayasinghe, Yock Sin Lay, Dawn Xiao Tian Liu, Chang Yu Lee, Chang Gao, Brendon Zhijie Yeo, Faith Yuan Xin How, Rebecca Carissa Prajogo, Dong Van Hoang, Hong Anh Le, Thach Tuan Pham, Boya Peng, Cao Dai Phung, Daniel G Tenen, Minh T N Le
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引用次数: 0
Abstract
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.
免疫疗法已成为癌症治疗的主流,但其疗效却受到免疫相关不良反应风险的制约。在这项研究中,我们提出了一种基于纳米颗粒的给药系统,它能提高免疫调节配体的疗效,同时限制全身毒性。我们证明,细胞外囊泡(EVs)是细胞释放的脂质双分子层封闭颗粒,可通过 iEDDA 介导的共轭作用有效地在其表面显示多种免疫调节配体。在EV表面显示免疫调节配体可大大提高信号效力,尤其是对肿瘤坏死因子受体超家族(TNFRSF)激动剂而言,EV表面显示可作为一种独立于FcγR的替代方法,诱导配体多聚化和有效的受体交联。在多种转移性癌症模型中,显示免疫治疗配体互补组合的 EV 能够使肿瘤免疫环境向抗肿瘤表型转变,并在更大程度上抑制肿瘤负荷和提高生存率,其效果优于同等剂量的游离配体。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,它能以更低的剂量和更小的副作用促进卓越的抗肿瘤反应。
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.