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pH-sensitive tumor-tropism hybrid membrane-coated nanoparticles for reprogramming the tumor microenvironment and boosting the antitumor immunity

肿瘤微环境 免疫系统 重编程 癌症研究 免疫疗法 癌症免疫疗法 癌细胞 化学 生物 细胞生物学 癌症 免疫学 细胞 生物化学 遗传学
作者
Jie Zhang,Liwen Wei,Xiaocao Ma,Jingguo Wang,Siping Liang,Kang Chen,Minhao Wu,Niu Li,Yuanqing Zhang
出处
期刊:Acta Biomaterialia [Elsevier]
卷期号:166: 470-484 被引量:13
标识
DOI:10.1016/j.actbio.2023.05.040
摘要

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. Metabolic 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.
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