三阴性乳腺癌（TNBC）仍然是一种具有高致死率和不良预后的强大敌手。肿瘤微环境由各种组分组成，其中肿瘤浸润的树突状细胞（TIDCs）和肿瘤相关巨噬细胞（TAMs）被认为是介导免疫应答的关键因素。克服TIDCs和TAMs的耐药性对于诱导强有力和持久性的免疫反应以抵抗癌细胞至关重要。在本研究中，我们开发了一种pH/ROS响应型微核酸155（miR155）纳米复合物（MiR@PCPmP NPs），用于高效TNBC免疫治疗的TIDCs和TAMs重编程。该纳米平台基于一个pH/ROS可切割的共聚物聚乙二醇-羧基二甲基马来酸酯-聚乙烯亚胺-过草酸酯-聚ε-己内酯接枝甘露糖基（PEG-CDM-PEI[Man]-ox-PCL），它与miRNA自组装形成纳米复合物。在肿瘤微环境中，纳米复合物通过PEG脱离和曼诺糖暴露显示出选择性地被TIDCs和TAMs细胞摄取，然后实现了高效的内体逃逸、细胞质miR155释放以及TIDCs和TAMs的二重编程。我们的结果表明，MiR@PCPmP NPs显著改善了4T1肿瘤小鼠体内高浸润的CD8+ T细胞的抗肿瘤免疫反应，同时抑制了免疫抑制性成分。此外，纳米颗粒有效地抑制了原发肿瘤和肺转移结节，而没有明显的全身毒性。该研究突出了使用miR155纳米复合物进行TIDCs和TAMs二重编程作为TNBC免疫治疗的有研究前景的策略，并具有将该策略转化应用于其他具有类似微环境的癌症的潜力。© 2023版权所有。Elsevier B.V.发表。

Triple negative breast cancer (TNBC) remains to be a formidable adversary with high mortality and unfavorable prognosis. Tumor microenvironment comprises of various constituents, among them, tumor infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) which have been recognized as pivotal factors responsible for mediating immune responses. Overcoming the refractory properties of TIDCs and TAMs is critical for inducing a robust and sustained immune response against cancer cells. In this study, pH/ROS-responsive microRNA-155 (miR155) nanocomplexes (MiR@PCPmP NPs) were developed to reprogram TIDCs and TAMs for efficient TNBC immunotherapy. This nanoplatform was based on a pH/ROS cleavable copolymer of poly(ethylene glycol)-carboxydimethyl maleate-poly(ethyleneimine)-peroxalate ester-poly(ε-caprolactone) grafted with mannose moieties (PEG-CDM-PEI[Man]-ox-PCL) which self-assembled with miRNA to form nanocomplexes. In the tumor microenvironment, the nanocomplexes showed selective cellular uptake by TIDCs and TAMs through PEG detachment and mannose exposure, followed by efficient endosomal escape, cytosolic miR155 release, and the dual-reprogramming of TIDCs and TAMs. Our results showed that MiR@PCPmP NPs significantly improved antitumor immune responses with highly infiltrating CD8+ T cells while restraining immunosuppressive components in 4T1 tumor-bearing mice. Furthermore, the nanoparticles effectively suppressed both primary tumors and pulmonary metastatic nodules without obvious systemic toxicity. This research highlights the potential of dual-reprogramming of TIDCs and TAMs with the miR155 nanocomplexes as a promising strategy for TNBC immunotherapy, with potential for translation to other cancers with a similar microenvironment.Copyright © 2023. Published by Elsevier B.V.