The low targeting of immunity regulators & chemotherapy drugs and immune tolerance in the tumor microenvironment significantly hindered the chemo-immunotherapy effect. In this work, an MMP-2/GSH-responsive nanobomb loading Resiquimod (R848) and prodrug Cisplatin (Pt) with hierarchical drug delivery and tumor associated macrophages (TAMs) polarization traits was designed for improved chemo-immunotherapy. The Pt-carrying dendrimers penetrate the depth of tumor tissues under MMP-2 and activate the cytotoxicity of Pt prodrug in response to GSH, causing effective tumor damage and enhancing immunogenicity. Meanwhile, R848 is effectively uptake by TAMs, which were re-educated and then greatly relieved immune resistance. and results collectively revealed that the nanosystem could not only overcome the barrier of tumor penetration and the heterogeneity action sites of drugs but also re-educate TAMs and suppress immune evasion via activating extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signal pathway regulated by heparin binding EGF like growth factor () gene. The gene silencing or knockout and demonstrated that could regulate the re-education of TAMs and the progression of tumors.

中文翻译：

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MMP-2/GSH 响应纳米炸弹通过调节 hbegf 激活的 ERK/MAPK 信号通路进行分级递送和 TAM 再教育，用于肿瘤化疗免疫治疗


免疫调节剂和化疗药物的低靶向性以及肿瘤微环境中的免疫耐受性显着阻碍了化疗免疫治疗的效果。在这项工作中，设计了一种负载 Resiquimod (R848) 和前药顺铂 (Pt) 的 MMP-2/GSH 响应纳米炸弹，具有分级药物递送和肿瘤相关巨噬细胞 (TAM) 极化特性，用于改善化学免疫治疗。携带 Pt 的树枝状大分子渗透到 MMP-2 下的肿瘤组织深处，并响应 GSH 激活 Pt 前药的细胞毒性，造成有效的肿瘤损伤并增强免疫原性。同时，R848被TAM有效摄取，对其进行再教育，大大缓解了免疫抵抗力。结果表明，纳米系统不仅可以克服肿瘤渗透障碍和药物作用位点的异质性，还可以通过激活细胞外信号调节激酶/丝裂原激活蛋白激酶（ERK/MAPK）来重新教育 TAM 并抑制免疫逃逸。 ）信号通路受肝素结合EGF样生长因子（）基因调节。基因沉默或敲除被证明可以调节 TAM 的再教育和肿瘤的进展。