膀胱癌（BCa）是全世界最常见的恶性肿瘤之一。尽管经过多方努力，BCa患者的5年生存率近年来仍保持不变。约 74% 的 BCa 组织样本中发现表皮生长因子受体 (EGFR) 过度表达；然而，目前基于 EGFR 的靶向治疗对 BCa 患者几乎没有什么好处，因为 EGFR 下游通路似乎被其他受体酪氨酸激酶 (RTK) 绕过。在这项研究中，确定了两种天然产物，即雷公藤内酯醇 (TPL) 和橙皮苷 (HSP)，它们能够靶向并抑制 BCa 中的 EGFR 及其下游 PI3K/AKT 通路。为了协同结合雷公藤甲素和橙皮苷，采用琥珀酸连接体将它们缀合并形成两亲性 TPL-HSP EGFR 靶向前药 (THE)，该前药进一步自组装生成纳米颗粒 (THE NP)。这些纳米粒子允许靶向递送雷公藤内酯醇和橙皮苷，并在体外和体内同时抑制 EGFR 和 PI3K/AKT。这项研究提供了一种有前途的 EGFR 靶向递送方法，具有 EGFR 和 PI3K/AKT 的双重抑制作用，同时还表现出高载药量和低毒性。我们的配方可能是通过 EGFR 靶向疗法提供用于 BCa 治疗的天然产品的合适选择。© 2023 作者。河南大学和约翰·威利出版的《探索》

Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy.© 2023 The Authors. Exploration published by Henan University and John Wiley & Sons Australia, Ltd.