Abstract：
Cancer immunotherapy has emerged as a promising approach to cancer treatment in recent years. The physical and chemical properties of nanocarriers are critical factors that regulate the immune activation of antigen-presenting cells (APCs) in the tumor microenvironment (TME). Herein, we extensively investigated the behavior of liposome nanoparticles (Lipo-NPs) with different elasticities, focusing on their interaction with immune cells and their transport mechanisms from tumors to tumor-draining lymph nodes (tdLNs). Successfully preparing Lipo-NPs with distinct elastic properties, their varied behaviors were observed, concerning immune cell interaction. Soft Lipo-NPs exhibited an affinity to cell membranes, while those with medium elasticity facilitated the cargo delivery to macrophages through membrane fusion. Conversely, hard Lipo-NPs enter macrophages via classical cellular uptake pathways. Additionally, it was noted that softer Lipo-NPs displayed superior transport to tdLNs in vivo, attributed to their deformable nature with lower elasticity. As a result, the medium elastic Lipo-NPs with agonists (cGAMP), by activating the STING pathway and enhancing transport to tdLNs, promoted abundant infiltration of tumor-infiltrating lymphocytes (TILs), leading to notable antitumor effects and extended survival in a melanoma mouse model. Furthermore, this study highlighted the potential synergistic effect of medium elasticity Lipo-NPs with immune checkpoint blockade (ICB) therapy in preventing tumor immune evasion. These findings hold promise for guiding immune-targeted delivery systems in cancer immunotherapy, particularly in vaccine design for tdLNs targeting and eradicating metastasis within tdLNs.
摘要：
近年来，癌症免疫疗法已成为一种有前途的癌症治疗方法。纳米载体的物理和化学性质是调节肿瘤微环境（TME）中抗原呈递细胞（APC）免疫激活的关键因素。在这里，我们广泛研究了具有不同弹性的脂质体纳米颗粒（Lipo-NPs）的行为，重点关注它们与免疫细胞的相互作用及其从肿瘤到肿瘤引流淋巴结（tdLNs）的转运机制。成功制备具有不同弹性性质的Lipo-NP，观察到他们的不同行为，关于免疫细胞相互作用。软脂-NP表现出对细胞膜的亲和力，而那些具有中等弹性的人通过膜融合促进了向巨噬细胞的货物递送。相反，硬Lipo-NP通过经典的细胞摄取途径进入巨噬细胞。此外,值得注意的是，较软的Lipo-NPs在体内表现出优于tdLNs的转运，归因于它们具有较低弹性的可变形性质。因此,带激动剂的中等弹性Lipo-NP（cGAMP），通过激活STING途径并增强到tdLN的转运，促进肿瘤浸润淋巴细胞（TIL）的大量浸润，在黑色素瘤小鼠模型中导致显著的抗肿瘤作用和延长的生存期。此外，这项研究强调了中等弹性Lipo-NP与免疫检查点阻断(ICB)治疗在预防肿瘤免疫逃避方面的潜在协同作用.这些发现有望指导癌症免疫治疗中的免疫靶向递送系统。特别是在针对tdLN靶向和根除tdLN内转移的疫苗设计中。
