pH-Sensitive Tumor-Tropism Hybrid Membrane-Coated Nanoparticles for Reprogramming the Tumor Microenvironment and Boosting the Antitumor Immunity.
pH-Sensitive Tumor-Tropism Hybrid Membrane-Coated Nanoparticles for Reprogramming the Tumor Microenvironment and Boosting the Antitumor Immunity.
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DOI：
10.1016/j.actbio.2023.05.040
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发表时间：
2023-05
影响因子：
9.7
通讯作者：
Jie Zhang;Liwen Wei;Xiaocao Ma;Jingguo Wang;Siping Liang;Kang Chen;Minhao Wu;Li Niu;Yuanqing Zhang
中科院分区：
文献类型：
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作者：
Jie Zhang;Liwen Wei;Xiaocao Ma;Jingguo Wang;Siping Liang;Kang Chen;Minhao Wu;Li Niu;Yuanqing Zhang
代谢失调不仅导致肿瘤的发生，而且导致肿瘤免疫微环境(TIME)，这给化疗和免疫治疗带来了巨大的挑战。靶向代谢重编程是最近出现的一种有希望的癌症治疗策略，但对实体肿瘤的杀伤力似乎相当有限，部分原因是小分子药物的溶解性较差。在这里，我们构建了一种多功能的仿生纳米平台(简称HM-BPT)，它使用pH敏感的肿瘤亲和性杂化薄膜包裹的氧化锰纳米颗粒来传递谷氨酰胺代谢抑制剂BPTES。基本上，由间充质干细胞膜(MSCM)和pH敏感脂质体(PSL)组成的杂交膜能够使仿生纳米平台靶向TME，并在内吞后逃脱内/溶酶体。结果表明，HM-BPT对4T1小鼠移植瘤有明显的抑瘤作用，细胞毒性T淋巴细胞(CTL)浸润，巨噬细胞M1表型复极化和干扰素基因刺激物(STING)通路激活。此外，谷胱甘肽(GSH)的耗尽和氧气(O2)的供应协同改善TME的免疫抑制状态，增强强大的抗肿瘤免疫反应。总体而言，我们的研究探索了TME重新编程和免疫激活的集成治疗平台，为癌症联合治疗提供了巨大的希望。重要的陈述：代谢异常和肿瘤免疫微环境(TIME)导致对传统治疗的低反应，最终导致难治性恶性肿瘤。在目前的工作中，开发了一种仿生纳米平台(HM-BPT)，用于TME代谢重新编程，以利于免疫治疗。特别是，杂化膜伪装赋予了纳米平台TME靶向性、内切/溶酶体逃逸和敏感的释放特性。探讨了杂化膜融合率对细胞摄取和细胞活力的影响，为未来生物活性纳米材料的开发提供了有益的参考。在4T1异种移植模型中，静脉注射HM-BPT显著减轻了肿瘤负担，恢复了固有和获得性免疫激活。总之，所创建的HM-BPT系统有可能成为结合癌症治疗的一个有前途的纳米平台。
Metabolic dysregulation contributes not only to cancer development but also to a tumor immune microenvironment (TIME), which poses great challenges to chemo- and immunotherapy. Targeting metabolic reprogramming has recently emerged as a promising strategy for cancer treatment, but the lethality against solid tumors appears to be fairly restricted, partially due to the poor solubility of small molecule drugs. Herein, we construct a versatile biomimetic nanoplatform (referred to as HM-BPT) employing pH-sensitive tumor-tropism hybrid membrane-coated Manganese oxide (MnO2) nanoparticles for the delivery of BPTES, a glutamine metabolism inhibitor. Basically, hybrid membranes consisting of mesenchymal stem cell membranes (MSCm) and pH-sensitive liposomes (pSL) enable the biomimetic nanoplatform to target TME and escape from endo/lysosomes after endocytosis. The results reveal that HM-BPT treatment leads to remarkable tumor inhibition, cytotoxic T lymphocyte (CTL) infiltration, as well as M1 phenotype repolarization and stimulator of IFN genes (STING) pathway activation in macrophages in a 4T1 xenograft model. Furthermore, glutathione (GSH) depletion and oxygen (O2) supply synergistically ameliorate the immunosuppressive status of the TME, boosting potent antitumor immune responses. Overall, our study explores an integrated therapeutic platform for TME reprogramming and immune activation, offering tremendous promise for cancer combination therapy.Statement of significanceMetabolic abnormalities and the tumor immune microenvironment (TIME) lead to hyporesponsiveness to conventional therapies, ultimately resulting in refractory malignancies. In the current work, a biomimetic nanoplatform (HM-BPT) was developed for TME metabolic reprogramming in favor of immunotherapy. Particularly, hybrid membrane camouflage endowed the nanoplatform with TME targeting, endo/lysosomal escape, and sensitive release properties. The impact of hybrid membrane fusion ratio on cellular uptake and cell viability was explored, yielding beneficial references for the future development of bioactive nanomaterials. Intravenous administration of HM-BPT substantially relieved tumor burden and restored innate and acquired immune activation in 4T1 xenograft models. In conclusion, the created HM-BPT system has the potential to be a promising nanoplatform for combining cancer therapies.