抗坏血酸（AA）因其在T细胞依赖性抗肿瘤免疫中的新潜力而备受关注。然而，过早的血液清除和免疫“冷”肿瘤严重损害了其免疫治疗结果。因此，免疫抑制肿瘤微环境（TME）的逆转一直是提高基于AA的免疫疗法有效性的前提，这取决于先进的AA递送和扩增的免疫激活策略。
该文中，基于AA固定化金属-有机框架（MOF）在硼替佐米（BTZ）负载的镁掺杂介孔二氧化硅（MMS）纳米载体上的门控，研究人员精心设计了一种新型大肠杆菌（E.coli）外膜囊泡（OMV）-红细胞（RBC）混合膜（ERm）-伪装免疫调节纳米塔，该纳米塔可以通过化疗辅助抗坏血酸介导的免疫疗法（CAMIT）实现免疫景观重塑。
一旦达到酸性TME，纳米塔内对酸性敏感的MOF守门人和MMS核心就会发生逐步降解，从而使肿瘤选择性地依次释放AA和BTZ。释放的BTZ可以引起强大的免疫原性细胞死亡（ICD），与OMV联合协同促进树突状细胞（DC）成熟，并最终与Mg2+一起增加T细胞肿瘤浸润。AA进一步激活T细胞大军，表现出显著的抗肿瘤和抗转移性能。此外，CD8缺陷小鼠模型揭示了基于AA的CAMIT策略的T细胞依赖性免疫机制。
除了提供一种多功能仿生混合纳米载体外，该研究还有望建立一种基于多组分驱动纳米转塔的新的免疫调节强化策略，用于高效T细胞激活增强协同AA免疫疗法。
附：英文原文
Title: Hybrid Membrane-Camouflaged Biomimetic Immunomodulatory Nanoturrets with Sequential Multidrug Release for Potentiating T Cell-Mediated Anticancer Immunity
Author: Wenjing Yao, Weiwei Liu, Fanshu Su, Junran Wang, Hao Li, Minghao Sun, Yuanyuan Ma, Yingjie Xu, Danrui Li, Yazhou Wang, Nan Lu, Shenghong Ju, Wenpei Fan
Issue&Volume: June 29, 2024
Abstract: Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically “cold” tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal–organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
DOI: 10.1021/jacs.4c04840
