Abstract：
Targeting macrophages to regulate the tumor microenvironment is a promising strategy for treating cancer. This study developed a stable nano drug (PAP-SeNPs) using Se nanoparticles (SeNPs) and the Pholiota adiposa polysaccharide component (PAP-1a) and reported their physical stability, M2-like macrophages targeting efficacy and anti-hepatoma immunotherapy potential, as well as their molecular mechanisms. Furthermore, the zero-valent and well-dispersed spherical PAP-SeNPs were also successfully synthesized with an average size of 55.84 nm and a negative ζ-potential of -51.45 mV. Moreover, it was observed that the prepared PAP-SeNPs were stable for 28 days at 4 °C. Intravital imaging highlighted that PAP-SeNPs had the dual effect of targeting desirable immune organs and tumors. In vitro analyses showed that the PAP-SeNPs polarized M2-like macrophages towards the M1 phenotype to induce hepatoma cell death, triggered by the time-dependent lysosomal endocytosis in macrophages. Mechanistically, PAP-SeNPs significantly activated the Tlr4/Myd88/NF-κB axis to transform tumor-promoting macrophages into tumor-inhibiting macrophages and successfully initiated antitumor immunotherapy. Furthermore, PAP-SeNPs also enhanced CD3+CD4+ T cells and CD3+CD8+ T cells, thereby further stimulating anti-hepatoma immune responses. These results suggest that the developed PAP-SeNPs is a promising immunostimulant that can assist hepatoma therapy.
摘要：
靶向巨噬细胞以调节肿瘤微环境是治疗癌症的有希望的策略。这项研究开发了一种稳定的纳米药物（PAP-SeNPs）使用硒纳米颗粒（SeNPs）和pholiota脂肪多糖成分（PAP-1a），并报道了它们的物理稳定性，M2样巨噬细胞靶向疗效和抗肝癌免疫治疗潜力，以及它们的分子机制。此外，还成功合成了零价且分散良好的球形PAP-SeNP，其平均尺寸为55.84nm，负ζ电位为-51.45mV。此外，观察到制备的PAP-SeNPs在4°C下稳定28天。体内成像强调PAP-SeNPs具有靶向期望的免疫器官和肿瘤的双重作用。体外分析表明，PAP-SeNPs极化M2样巨噬细胞向M1表型诱导肝癌细胞死亡，由巨噬细胞的时间依赖性溶酶体内吞作用引发。机械上,PAP-SeNPs显著激活Tlr4/Myd88/NF-κB轴，将促进肿瘤的巨噬细胞转化为抑制肿瘤的巨噬细胞，并成功启动抗肿瘤免疫治疗。此外，PAP-SeNPs还增强了CD3+CD4+T细胞和CD3+CD8+T细胞，从而进一步刺激抗肝癌免疫应答。这些结果表明，开发的PAP-SeNPs是一种有前途的免疫刺激剂，可以帮助肝癌治疗。
