铁死亡和坏死性凋亡产生自体肿瘤细胞裂解物与联合免疫佐剂共同递送作为抗肿瘤免疫的个性化原位纳米疫苗,ACS Nano

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铁死亡和坏死性凋亡产生自体肿瘤细胞裂解物与联合免疫佐剂共同递送作为抗肿瘤免疫的个性化原位纳米疫苗
ACS Nano ( IF 15.8 ) Pub Date : 2023-07-19 , DOI: 10.1021/acsnano.3c00901
Wanrui Shi ₁ , Wenjie Feng ₁ , Siyuan Li ₁ , Yanqi Cui ₁ , Shuwei Liu ₂ , Huan Jiang ₃ , Yi Liu ₁ , Hao Zhang _{1,

2,

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Affiliation

基于纳米疫苗的免疫治疗被认为是刺激宿主免疫系统识别和消灭肿瘤细胞以及建立长期免疫记忆以防止肿瘤复发和转移的主要支柱。然而，抗原的弱特异性和低交叉呈递以及肿瘤组织的免疫抑制微环境仍然是肿瘤纳米疫苗充分发挥治疗性能的主要障碍。在此，我们设计并构建了负载胞嘧啶鸟嘌呤二核苷酸（CpG）寡脱氧核苷酸（ODN）的羟基磷酸铝纳米颗粒，该纳米颗粒被铁紫草素金属酚网络（MPN）覆盖（Alum-CpG@Fe-紫草素纳米粒子）作为个性化原位抗肿瘤纳米疫苗免疫。被肿瘤细胞内化后，Fe-Shikonin MPNs 的外壳将分解为 Fe ²⁺和 Shikonin，通过铁死亡和坏死性凋亡引发肿瘤细胞的免疫原性细胞死亡。然后，垂死的肿瘤细胞释放的自体肿瘤细胞裂解物将被Alum NPs吸收，并与CpG ODN在时间和空间上共同递送至专业抗原呈递细胞，以激活多步级联抗肿瘤免疫反应，包括树突状细胞成熟、抗原交叉呈递、自然杀伤细胞和细胞毒性 T 淋巴细胞浸润，以及肿瘤相关巨噬细胞复极化。受益于 Alum NPs、CpG ODN 和 Fe-Shikonin MPNs 的协同作用，我们的 Alum-CpG@Fe-Shikonin NPs 在根除原发肿瘤方面表现出强烈的细胞毒性和精确的选择性，对抑制远处肿瘤具有强烈的远隔作用，并且具有长效作用。长期免疫记忆作用可预防肿瘤转移和复发。由于我们的报告提供了一种原位充分利用自体肿瘤细胞裂解物的可行策略，该裂解物呈现患者个人表位的全谱，而无需复杂的离体过程，例如提取、纯化和测序，因此它可能会促进肿瘤细胞裂解物的发展。用于抗肿瘤免疫的个性化纳米疫苗。

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Ferroptosis and Necroptosis Produced Autologous Tumor Cell Lysates Co-Delivering with Combined Immnoadjuvants as Personalized In Situ Nanovaccines for Antitumor Immunity

Nanovaccine-based immunotherapy has been considered as a major pillar to stimulate the host immune system to recognize and eradicate tumor cells as well as establish a long-term immune memory to prevent tumor relapse and metastasis. However, the weak specificity and low cross-presentation of antigens, as well as the immunosuppressive microenvironments of tumor tissues, are still the major obstacles on exerting the therapeutic performance of tumor nanovaccines sufficiently. Herein, we design and construct cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-loaded aluminum hydroxyphosphate nanoparticles covered by Fe-Shikonin metal-phenolic networks (MPNs) (Alum-CpG@Fe-Shikonin NPs) as personalized in situ nanovaccines for antitumor immunity. Upon internalization by tumor cells, the shell of Fe-Shikonin MPNs will disassemble into Fe²⁺ and Shikonin to elicit the immunogenic cell death of tumor cells through ferroptosis and necroptosis. Then, dying tumor cell-released autologous tumor cell lysates will be absorbed by Alum NPs and codelivered with CpG ODN to professional antigen-presenting cells temporally and spatially to activate multistep cascade antitumor immune responses, including dendritic cell maturation, antigen cross-presentation, natural killer cell and cytotoxic T lymphocyte infiltrations, and tumor-associated macrophage repolarization. Benefiting from the synergistic effects of Alum NPs, CpG ODN, and Fe-Shikonin MPNs, our Alum-CpG@Fe-Shikonin NPs exhibit drastic cytotoxicity and accurate selectivity on eradicating primary tumor, strong abscopal effect on inhibiting distant tumor, and a long-term immune memory effect on preventing tumor metastasis and recurrence. Because our report provides a feasible strategy to in situ make full use of autologous tumor cell lysates, which present an entire spectrum of the patient’s personal epitopes without complicated ex vivo processes, such as extraction, purification, and sequencing, it may promote the development of personalized nanovaccines for antitumor immunity.

更新日期：2023-07-19

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