用于增强癌症免疫疗法的 STING 激活层状双氢氧化物纳米佐剂

IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Lirui Jia , Yang Qin , Xin Li , Hongzhuo Liu , Zhonggui He , Yongjun Wang
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引用次数: 0

摘要

癌症疫苗是一种前景广阔的肿瘤治疗策略,但其有效性往往受到抗原靶向性不理想、细胞免疫诱导不足以及免疫抑制性肿瘤微环境的影响。要应对这些挑战,需要先进的递送系统和强效佐剂,但目前获批的人用疫苗佐剂种类有限,能激发强大细胞免疫反应的佐剂更是少之又少。在这项工作中,我们将 STING 激动剂锰整合到层状双氢氧化物纳米支架中,并包裹模型抗原卵清蛋白(OVA),从而设计出一种独特的自佐剂平台(MLDHs)。MLDHs 平台包括掺锰 MgAl-LDH(MLMA)和掺锰 MgFe-LDH(MLMF)。皮下注射后,OVA/MLDHs 会在淋巴结(LNs)内聚集,并被驻留的抗原递呈细胞内化。MLDHs 的内质体降解促进了抗原和 Mn2+ 的胞浆释放,促进了交叉呈递并触发了 STING 通路,进而诱导了针对肿瘤的强效细胞免疫反应。值得注意的是,与 OVA/MLMA 相比,OVA/MLMF 能诱导更强的 M1 巨噬细胞极化和肿瘤浸润淋巴细胞内更强的 T 细胞反应,从而使携带 B16F10-OVA 的小鼠的肿瘤显著消退,且不良反应极小。此外,将 MLMF 与血管破坏剂 Vadimezan 结合使用,还能破坏肿瘤的中心区域(该区域通常对免疫细胞浸润具有抵抗力),从而进一步延长肿瘤小鼠的生存期。这种创新策略可能会显示出改进癌症免疫疗法的巨大潜力,并为未来更有效的治疗方法带来希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
STING-activating layered double hydroxide nano-adjuvants for enhanced cancer immunotherapy
Cancer vaccines represent a promising therapeutic strategy in oncology, yet their effectiveness is often hampered by suboptimal antigen targeting, insufficient induction of cellular immunity, and the immunosuppressive tumor microenvironment. Advanced delivery systems and potent adjuvants are needed to address these challenges, though a restricted range of adjuvants for human vaccines that are approved, and even fewer are capable of stimulating robust cellular immune response. In this work, we engineered a unique self-adjuvanted platform (MLDHs) by integrating STING agonists manganese into a layered double hydroxide nano-scaffold, encapsulating the model antigen ovalbumin (OVA). The MLDHs platform encompasses Mn-doped MgAl-LDH (MLMA) and Mn-doped MgFe-LDH (MLMF). Upon subcutaneous injection, OVA/MLDHs specifically accumulated within lymph nodes (LNs), where they were internalized by resident antigen-presenting cells. The endosomal degradation of MLDHs facilitated the cytoplasmic release of antigen and Mn2+, promoting cross-presentation and triggering the STING pathway, which in turn induced a potent cellular immune response against tumors. Notably, OVA/MLMF induced stronger M1 macrophage polarization and a more potent T-cell response within tumor-infiltrating lymphocytes compared to OVA/MLMA, leading to significant tumor regression in B16F10-OVA bearing mice with minimal adverse effects. Additionally, combining MLMF with the vascular disrupting agent Vadimezan disrupted the tumor's central region, typically resistant to immune cell infiltration, further extending survival in tumor-bearing mice. This innovative strategy may show great potential for improving cancer immunotherapy and offers hope for more effective treatments in the future.
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来源期刊
Biomaterials
Biomaterials 工程技术-材料科学:生物材料
CiteScore
26.00
自引率
2.90%
发文量
565
审稿时长
46 days
期刊介绍: Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.
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