School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
College of Chemistry and Materials Science, The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Normal University, Shanghai, 200234, China.
Adv Mater. 2024 Jul;36(27):e2313097. doi: 10.1002/adma.202313097. Epub 2024 Apr 29.
Therapy-induced immunogenic cell death (ICD) can initiate both innate and adaptive immune responses for amplified anti-tumor efficacy. However, dying cell-released ICD signals are prone to being sequestered by the TIM-3 receptors on dendritic cell (DC) surfaces, preventing immune surveillance. Herein, dismantlable coronated nanoparticles (NPs) are fabricated as a type of spatiotemporally controlled nanocarriers for coupling tumor cell-mediated ICD induction to DC-mediated immune sensing. These NPs are loaded with an ICD inducer, mitoxantrone (MTO), and wrapped by a redox-labile anti-TIM-3 (αTIM-3) antibody corona, forming a separable core-shell structure. The antibody corona disintegrates under high levels of extracellular reactive oxygen species in the tumor microenvironment, exposing the MTO-loaded NP core for ICD induction and releasing functional αTIM-3 molecules for DC sensitization. Systemic administration of the coronated NPs augments DC maturation, promotes cytotoxic T cell recruitment, enhances tumor susceptibility to immune checkpoint blockade, and prevents the side effects of MTO. This study develops a promising nanoplatform to unleash the potential of host immunity in cancer therapy.
治疗诱导的免疫原性细胞死亡（ICD）可以引发先天和适应性免疫反应，从而增强抗肿瘤疗效。然而，死亡细胞释放的 ICD 信号容易被树突状细胞（DC）表面的 TIM-3 受体隔离，从而阻止免疫监视。在此，可拆解的冠冕状纳米颗粒（NPs）被制作为一种时空可控的纳米载体，用于将肿瘤细胞介导的 ICD 诱导与 DC 介导的免疫感应偶联。这些 NPs 负载 ICD 诱导剂米托蒽醌（MTO），并被氧化还原不稳定的抗 TIM-3（αTIM-3）抗体冠包裹，形成可分离的核壳结构。在肿瘤微环境中高水平的细胞外活性氧下，抗体冠会解体，暴露出负载 MTO 的 NP 核，从而引发 ICD 诱导，并释放功能型 αTIM-3 分子以敏化 DC。冠冕状 NPs 的全身给药可增强 DC 的成熟，促进细胞毒性 T 细胞募集，增强肿瘤对免疫检查点阻断的敏感性，并防止 MTO 的副作用。本研究开发了一种很有前途的纳米平台，可释放宿主免疫在癌症治疗中的潜力。
