Abstract：
Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.
摘要：
肿瘤疫苗已显示出适度的反应率，主要归因于它们向树突状细胞（DC）的低效递送，低交叉陈述，DC-内源性免疫抑制信号,和免疫抑制肿瘤微环境（TME）。这里,引流淋巴结（DLN）靶向和肿瘤靶向纳米疫苗被提出来解决这些限制，合成杂环类脂质（A18）和聚酯（BR647）以实现双靶向癌症免疫治疗。同时,掺入寡透明质酸(HA)和DMG-PEG2000-甘露糖,以制备用STAT3siRNA和模型抗原包封的双靶向纳米疫苗。纳米疫苗被设计为靶向DLN和肿瘤，促进货物进入细胞质。这些双靶向纳米疫苗改善了抗原呈递和DC成熟，激活干扰素基因刺激因子（STING）途径，增强了促凋亡作用，并刺激抗肿瘤免疫反应。此外,这些双靶向纳米疫苗克服了免疫抑制TME，减少免疫抑制细胞，并促进肿瘤相关中性粒细胞从N2向N1的极化。在四种诱导强大抗肿瘤反应的双靶向纳米疫苗中，杂环类脂质@聚酯杂化纳米疫苗（MALO@HBNS）显示出最有希望的结果。此外，涉及MALO@HBNS和抗PD-L1抗体的组合策略显示出非常强大的抗癌作用.这项工作介绍了一种用于抗肿瘤治疗的双靶向纳米疫苗平台，提示其与免疫检查点阻断的潜在组合作为一种全面的抗癌策略。
