褪黑激素和海藻酸钠是天然的活性化合物，据报道它们对接受癌症治疗的患者具有治疗效益。然而，这两种化合物都面临着重大挑战，包括在胃肠道中的物理、化学和生物代谢，这限制了它们在肿瘤部位达到治疗浓度的能力。此外，褪黑激素和海藻酸钠在体内作为辅助剂的效果受到通过消化系统给药途径和其在肿瘤终点的积累的影响。在本研究中，我们开发了一种口服纳米颗粒剂MNPs@C@F，它由修饰了壳聚糖的PLGA纳米颗粒组成，以促进肠道微褶皱细胞经皮转运，将褪黑激素和海藻酸钠传递到肿瘤中。实验结果表明，经阿霉素治疗后，肿瘤中的褪黑激素和海藻酸钠可以通过减少P-gp、Twist、HIF-1α和抗炎免疫细胞的表达，以及增加细胞毒性T细胞群体而调节肿瘤微环境。这导致了化疗药物的敏感性增加、远处器官的转移抑制和免疫性细胞死亡的促进。本研究证明了一种有利的褪黑激素和海藻酸钠共运输系统，能够直接减少三阴性乳腺癌的药物抗性和转移。版权所有 © 2023 Elsevier B.V. 发布。

Melatonin and fucoidan are naturally active compounds that have been reported to have therapeutic benefits for patients receiving cancer treatment. However, both compounds face significant challenges, including physical, chemical, and biological metabolisms in the gastrointestinal tract, which limit their ability to achieve therapeutic concentrations at the tumor site. Furthermore, the effectiveness of melatonin and fucoidan as adjuvants in vivo is influenced by the route of administration through the digestive system and their accumulation at the endpoint of the tumor. In this study, we developed an oral administration of nanoparticle, MNPs@C@F, that consisted of PLGA nanoparticles modified with chitosan, to promote intestinal microfold cell transcytosis for the delivery of melatonin and fucoidan into tumors. The experimental results indicated that melatonin and fucoidan in the tumors could regulate the tumor microenvironment by decreasing P-gp, Twist, HIF-1α, and anti-inflammatory immune cell expression, and increasing cytotoxic T cell populations following doxorubicin treatment. This resulted in an increase in chemo-drug sensitivity, inhibition of distant organ metastasis, and promotion of immunogenic cell death. This study demonstrates a favorable co-delivery system of melatonin and fucoidan to directly reduce drug resistance and metastasis in TNBC.Copyright © 2023. Published by Elsevier B.V.