Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery. However, the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application. Herein, a novel “core‒shell” co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid (UA) and polyphenol (EGCG) with the EpCAM-aptamer modification for hepatocellular carcinoma (HCC) synergistic treatment. As the nature products derived from food-plant, UA and EGCG had good anticancer activities and low toxicity. With the simple and “green” method, the nanodrugs had the advantages of good stability, pH-responsive and strong penetration of tumor tissues, which was expected to increase tumor cellular uptake, long circulation and effectively avoid the potential defects of traditional carriers. The nanocomplex exhibited the low cytotoxicity in the normal cells in vitro, good biosafety of organic tissues and efficient tumor accumulation in vivo. Importantly, UA combined with EGCG showed the immunotherapy by activating the innate immunity and acquired immunity resulting in significant synergistic therapeutic effect. The research could provide new ideas for the research and development of self-assembly delivery system in the future, and offer effective intervention strategies for clinical HCC treatment.

纳米技术已经成为实现高效化学试剂输送的理想方法。然而，大多数纳米载体的潜在毒性和内部代谢不清楚仍是临床应用的主要障碍。在此，基于熊果酸（UA）和多酚（EGCG）的天然来源，并经EpCAM适体修饰，构建了用于肝细胞癌（HCC）协同治疗的新型“核-壳”共组装无载体纳米系统。UA和EGCG作为来源于植物的天然产物，具有良好的抗癌活性和低毒性。通过简单且“绿色”的方法，纳米药物具有良好的稳定性，pH响应性和对肿瘤组织的强渗透性，有望增加肿瘤细胞的摄取，循环时间长，有效避免了传统航母的潜在缺陷。纳米复合物在正常细胞中显示出低细胞毒性在体外，有机组织具有良好的生物安全性，并在体内有效地积累了肿瘤。重要的是，UA与EGCG结合可通过激活先天免疫和获得性免疫来显示免疫疗法，从而产生明显的协同治疗效果。该研究可为今后自组装递送系统的研究提供新思路，并为临床肝癌治疗提供有效的干预策略。