T细胞免疫球蛋白粘膜（TIM）-3阻断改善了T细胞耗竭，并触发了树突状细胞（DC）炎性小体的激活，显示出在免疫检查点阻断（ICB）免疫疗法中具有巨大潜力。然而，药代动力学特性和肿瘤微环境中T细胞/DC浸润的情况仍然不如人意。在这里，我们开发了一种长非编码RNA（lncRNA）编辑的仿生纳米疫苗，结合抗-TIM-3以介导双重效应的抗原交叉呈递，并减弱T细胞免疫抑制，以增强ICB免疫疗法。利用长非编码RNA诱导的主要组织相容性抗原类I和肿瘤的免疫原性（LIMIT）编辑的肿瘤细胞膜，用于封装抗-TIM-3，形成LCCT。随后，将LCCT纳米颗粒嵌入基于海藻酸盐的水凝胶中，以抑制手术后肿瘤复发。LCCT保留了抗-TIM-3在DC和CD8+T细胞中的TIM-3阻断有效性（超过75%）。此外，集成的抗-TIM-3增强了LCCT在DC中的内吞作用（1.5倍），扩大了炎性小体激活和抗原交叉呈递。此外，这种与LCCT诱导的CD8+T细胞免疫抑制相协同的DC激活刺激了效应细胞和记忆前体CD8+T细胞对肿瘤的应对。这种lncRNA编辑的仿生纳米疫苗策略为改进当前的ICB免疫疗法带来了新的视角。版权所有 © 2023. Elsevier B.V.出版。

T-cell immunoglobulin mucin (TIM)-3 blockade ameliorates T cell exhaustion and triggers dendritic cell (DC) inflammasome activation, showing great potential in immune checkpoint blockade (ICB) immunotherapy. However, pharmacokinetic profile and T cell/DC infiltration in tumor microenvironment is still undesired. Here, we develop a long noncoding RNA (lncRNA)-edited biomimetic nanovaccine combined with anti-TIM-3 to mediate dual-effect antigen cross-presentation and dampen T cell immunosuppression for reinforced ICB immunotherapy. LncRNA inducing major histocompatibility complex I and immunogenicity of tumor (LIMIT)-edited tumor cell membrane is used to encapsulate anti-TIM-3, formulating LCCT. Afterward, LCCT nanoparticles are embedded into an alginate-based hydrogel for suppressing post-surgical tumor relapse. LCCT retains TIM-3 blockade efficacy of anti-TIM-3 in both DCs and CD8+ T cells (beyond 75%). Moreover, the integrated anti-TIM-3 augments endocytosis of LCCT in DCs (1.5-fold), amplifying inflammasome activation and antigen cross-presentation. Furthermore, such DC activation synergistic with LCCT-induced CD8+ T-cell dampened immunosuppression and direct cross-presentation stimulates effector and memory-precursor CD8+ T cells against tumors. This lncRNA-edited biomimetic nanovaccine strategy bring a new sight to improve current ICB immunotherapy.Copyright © 2023. Published by Elsevier B.V.