信使RNA（mRNA）疫苗在传染病预防和癌症免疫治疗中具有重要意义。然而，安全有效地利用先天免疫来刺激强大而持久的适应性免疫保护至关重要，但也具有挑战性。在这项研究中，我们合成了一个刺激响应型二价可电离脂质 (srBiv iLP) 文库，其中包含对酯酶、H2O2、细胞色素 P450、碱性磷酸酶、硝基还原酶或谷胱甘肽 (GSH) 作出响应的智能分子块，旨在利用生理线索来触发快速脂质降解，促进 mRNA 翻译，并通过活性氧 (ROS) 介导的增强诱导强大的抗肿瘤免疫。皮下免疫后，酯酶反应疫苗（eBiv-mVac）迅速内化并转运至引流淋巴结。然后，它在富含酯酶的抗原呈递细胞中经历快速脱腐和自焚降解，释放足够的用于抗原翻译的mRNA和大量反应性醌甲基化物以提高ROS水平。这导致先天免疫广泛激活，以增强 T 细胞反应，促使大量引发的抗原特异性 CD8 T 细胞循环并浸润到肿瘤中（与未接种疫苗的对照相比，>1000 倍），从而协调先天免疫和适应性免疫来控制肿瘤肿瘤生长。此外，通过进一步将我们的疫苗接种策略与免疫检查点阻断相结合，我们证明了一种协同作用，可以显着放大抗原特异性 CD8 T 细胞的数量和功能。反过来，这在异种移植和转移模型中产生了有效的全身抗肿瘤功效并延长了生存期，且完全缓解率很高。总体而言，我们的通用刺激响应 mRNA 递送平台有望为癌症免疫治疗的有效疫苗的设计以及基因编辑、蛋白质替代和细胞工程的有效和精确的载体的设计带来范式转变。

The messenger RNA (mRNA) vaccines hold great significance in contagion prevention and cancer immunotherapy. However, safely and effectively harnessing innate immunity to stimulate robust and durable adaptive immune protection is crucial, yet challenging. In this study, we synthesized a library of stimuli-responsive bivalent ionizable lipids (srBiv iLPs) with smart molecular blocks responsive to esterase, H2O2, cytochrome P450, alkaline phosphatase, nitroreductase, or glutathione (GSH), aiming to leverage physiological cues to trigger fast lipid degradation, promote mRNA translation, and induce robust antitumor immunity via reactive oxygen species (ROS)-mediated boosting. After subcutaneous immunization, esterase-responsive vaccine (eBiv-mVac) was rapidly internalized and transported into the draining lymph nodes. It then underwent fast decaging and self-immolative degradation in esterase-rich antigen-presenting cells, releasing sufficient mRNA for antigen translation and massive reactive quinone methides to elevate ROS levels. This resulted in broad activation of innate immunity to boost T cell response, prompting a large number of primed antigen-specific CD8+ T cells to circulate and infiltrate into tumors (>1000-fold versus unvaccinated control), thereby orchestrating innate and adaptive immunity to control tumor growth. Moreover, by further combining our vaccination strategy with immune checkpoint blockade, we demonstrated a synergism that significantly amplified the magnitude and function of antigen-specific CD8+ T cells. This, in turn, caused potent systemic antitumor efficacy and prolonged survival with high complete response rate in xenograft and metastasis models. Overall, our generalized stimuli-responsive mRNA delivery platform promises a paradigm shift in the design of potent vaccines for cancer immunotherapy, as well as effective and precise carriers for gene editing, protein replacement, and cell engineering.