癌症治疗中的复发和转移被认为是一个巨大的挑战。作为癌细胞的一个小的亚群体，癌症干细胞（CSCs）由于其耐药性和多向分化特性与肿瘤的转移和复发密切相关。在这里，我们开发了一种局部可注射的透明质酸（HA）复合水凝胶（HAAG），它能够靶向CSCs，并在肿瘤部位持续释放全反式视黄酸（ATRA）和金纳米颗粒（AuNPs）。复合水凝胶通过HA与CD44的特异性结合具有靶向CSCs的能力。ATRA被载入HA胶束中，用于诱导CSCs分化为正常癌细胞，而AuNPs被纳入水凝胶中用于光热治疗（PTT）。HAAG表现出良好的可注射性、光热性能和靶向CSCs的能力。HAAG不仅显著抑制了4T1小鼠乳腺癌细胞和4T1-CSCs的体外生长，还在4T1-CSC小鼠模型中有效抑制了肿瘤复发和转移。我们的研究提供了一种用于抑制乳腺癌复发和转移的局部分化联合PTT的新策略。版权所有© 2023 Elsevier B.V.发表。

Recurrence and metastasis have been recognized as a great challenge in cancer treatment. Cancer stem cells (CSCs), as a small subset of cancer cells, are closely associated with tumor metastasis and recurrence due to their resistance and multi-differentiation characteristics. Herein, we developed a local injectable hyaluronic acid (HA) composite hydrogel (HAAG) that targets CSCs, which can continuously release all-trans retinoic acid (ATRA) and gold nanoparticles (AuNPs) at tumor sites. The composite hydrogel was endowed with the ability to target CSCs through the specific binding of HA to CD44. ATRA was loaded into HA micelles to induce CSCs to differentiate into normal cancer cells, while AuNPs was incorporated into the hydrogel for photothermal therapy (PTT). HAAG exhibited good injectability, photothermal properties and CSCs targeting ability. HAAG not only significantly inhibited the growth of 4T1 mouse breast cancer cells and 4T1-CSCs in vitro, but also effectively inhibited tumor recurrence and metastasis in a 4T1-CSC mouse model in vivo. Our study provides a novel strategy of local differentiation combined with PTT for inhibiting the recurrence and metastasis of breast cancer.Copyright © 2023. Published by Elsevier B.V.