乳腺癌肿瘤微环境（TME）是缺氧的，可以促进肿瘤发展，包括侵袭和转移，并限制抗肿瘤治疗的疗效。一氧化氮（NO）可以扩张血管，有效缓解缺氧，并调节TME，有潜力改善抗肿瘤治疗疗效。本研究将壳聚糖（CO）和十八烷胺（ODA）通过二硫键连接，LinTT1肽连接到CO-SS-ODA上，以靶向肿瘤细胞和肿瘤内皮细胞。一氧化氮供体S-硝酰-N-乙酰青霉胺（SNAP）连接到CO上。多柔比星（DOX）被封装，并构建了对乳腺癌治疗具有GSH分级响应的聚合物胶束（TSCO-SS-ODA/DOX）。胶束在不同GSH浓度下具有不同的药物释放反应。在内皮细胞中，胶束能快速释放NO。在肿瘤细胞中，二硫键能迅速断裂，释放DOX以有效杀灭肿瘤细胞。二硫键对内皮细胞的GSH浓度不敏感，其释放DOX较少。胶束对内皮细胞的杀伤效应远低于对肿瘤细胞的效应。药物输送系统的细胞选择性药物释放可以实现安全有效的治疗。具备出色靶向肿瘤的能力，TSCO-SS-ODA/DOX可以缓解肿瘤缺氧，减少M2巨噬细胞的浸润，增加M1巨噬细胞的浸润，并重塑TME。值得注意的是，TSCO-SS-ODA/DOX可以显著抑制原发肿瘤的生长，并有效抑制肿瘤转移。本药物输送系统为有效治疗乳腺癌提供了潜在解决方案。

The tumor microenvironment (TME) of breast cancer is hypoxic, which can promote tumor progression, including invasion and metastasis, and limit the efficacy of anti-tumor treatment. Nitric oxide (NO) can dilate blood vessels, effectively alleviate hypoxia, and regulate the TME, which has the potential to improve the anti-tumor therapeutic efficacy. Here, chitosan (CO) and octadecylamine (ODA) were linked by the disulfide bond, and the LinTT1 peptide was linked onto CO-SS-ODA for targeting tumor cells and endothelial cells in tumors. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) was connected to CO. Doxorubicin (DOX) was encapsulated, and GSH hierarchically responsive polymer micelles (TSCO-SS-ODA/DOX) were constructed for the treatment of breast cancer. The micelles had differently responsive drug release in different GSH concentrations. In endothelial cells, the micelles rapidly responded to release NO. In tumor cells, the disulfide bond rapidly broke and released DOX to effectively kill tumor cells. The disulfide bond was not sensitive to GSH concentration in endothelial cells, which had less release of DOX. The killing effect of the micelles to endothelial cells was much lower than that to tumor cells. The cell selective drug release of the drug delivery systems enabled safe and effective treatment of drugs. TSCO-SS-ODA/DOX, which had the excellent ability to target tumors, can alleviate tumor hypoxia, decrease the infiltration of M2 macrophages in tumors, increase the infiltration of M1 macrophages in tumors, and remodel the TME. Notably, TSCO-SS-ODA/DOX can significantly inhibit the growth of the primary tumor and effectively inhibit tumor metastasis. The drug delivery system provided a potential solution for effectively treating breast cancer.