涉及免疫检查点阻断（ICB）和其他药物的联合治疗是将免疫冷肿瘤转化为免疫热肿瘤以从免疫治疗中受益的潜在策略。为了实现药物协同作用，我们开发了同源癌细胞膜囊泡（CM）包被的金属有机框架（MOF）纳米递送平台，用于TLR7/8激动剂与表观遗传抑制剂的共递送。一种新型仿生共递送系统（MCM@UN ）是通过加载含溴结构域蛋白 4 (BRD4) 抑制剂的 MOF 纳米颗粒 UiO-66 构建的，然后用嵌入 3M-052 (M) 18 C 脂质尾部的同源癌细胞的膜囊泡进行包被。在三阴性乳腺癌（TNBC）小鼠模型和体外评估了 MCM@UN 的抗肿瘤免疫能力和肿瘤抑制作用。通过多色免疫荧光染色分析肿瘤免疫微环境。体外和体内数据表明MCM@UN特异性靶向TNBC细胞，在肿瘤生长抑制和抗肿瘤免疫活性方面优于游离药物。从机制上来说，MCM@UN阻断BRD4和PD-L1，促使垂死的肿瘤细胞解体并暴露肿瘤抗原。崩解的肿瘤细胞释放损伤相关分子模式（DAMP），招募树突状细胞（DC）来有效激活CD8 T细胞，介导有效且持久的抗肿瘤免疫。此外，MCM@UN 上的 TLR7/8 激动剂增强了淋巴细胞浸润和免疫原性细胞死亡，并减少了调节性 T 细胞 (Treg)。在临床标本上，我们发现浸润TNBC患者肿瘤组织的成熟DC与BRD4的表达呈负相关，这与动物模型中的结果一致。MCM@UN特异性靶向TNBC细胞，重塑肿瘤免疫微环境，抑制恶性TNBC 的行为。© 2024。作者。

Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor.A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining.In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model.MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.© 2024. The Author(s).