Charge-switchable nanoparticles enhance Cancer immunotherapy based on mitochondrial dynamic regulation and immunogenic cell death induction
Charge-switchable nanoparticles enhance Cancer immunotherapy based on mitochondrial dynamic regulation and immunogenic cell death induction
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电荷可切换纳米颗粒增强基于线粒体动态调节和免疫原性细胞死亡诱导的癌症免疫治疗
DOI：
10.1016/j.jconrel.2021.05.036
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发表时间：
2021
影响因子：
10.8
通讯作者：
Hu Haiyang
中科院分区：
文献类型：
--
作者：
Zhao Ming;Li Ji;Liu Jingwen;Xu Moxi;Ji Hongrui;Wu Siwen;Chen Dawei;Hu Haiyang
癌症免疫治疗已成为各种恶性肿瘤治疗的一种有希望的选择。不幸的是，免疫抑制肿瘤微环境（ITM）的存在和缺乏有效的递送策略限制了其进一步的应用。为了逆转ITM并开发一种有利的癌症免疫治疗递送系统，研究人员开发了双样电荷可切换纳米颗粒（shMFN1-NPs + DOX-NPs，称为MIX-NPs），分别选择性靶向肿瘤相关巨噬细胞（tam）和癌细胞。shMFN1-NPs （150 nm）和DOX-NPs （160 nm）均具有均匀的球形结构，并表现出良好的肿瘤组织积累。基于ph响应的核壳分离，纳米颗粒在循环时间和细胞摄取之间获得了良好的平衡。线粒体动力学通过调节一个新的信号网络参与巨噬细胞极化，包括从融合（m2 - tam）到线粒体裂变（m1 - tam）的调制。制备了靶向纳米颗粒shMFN1- nps的M2- tam，通过抑制线粒体融合，将shMFN1传递给M2到M1表型的tam。此外，DOX-NPs有效地触发了癌细胞的免疫原性细胞死亡（ICD），随后的树突状细胞（dc）成熟促进了CD8+T细胞的浸润和活化。MIX-NPs在皮下4T1肿瘤模型中表现出最强的抗肿瘤效果（TIR = 83%）。MIX-NPs抑制髓源性抑制细胞（MDSCs）和调节性T淋巴细胞（Tregs），进一步重塑ITM。综上所述，我们开发的药物递送策略逆转了ITM并激活了抗肿瘤免疫反应，为癌症免疫治疗提供了一种深刻的前瞻性治疗策略。
Cancer immunotherapy has emerged as a promising option for various malignant tumors therapy. Unfortunately, the existence of an immunosuppressive tumor microenvironment (ITM) and the absence of an effective delivery strategy limit its further application. To reverse the ITM and exploit a favorable delivery system for cancer immunotherapy, twin-like charge-switchable nanoparticles (shMFN1-NPs + DOX-NPs, termed as MIX-NPs) were developed to selectively target tumor-associated macrophages (TAMs) and cancer cells, respectively. The shMFN1-NPs (150 nm) and DOX-NPs (160 nm) both had uniform spherical-shaped structures and showed favorable tumor tissue accumulation. Based on the pH-responsive core-shell separation, the nanoparticles obtained an excellent balance between the circulation time and cellular uptake. Mitochondrial dynamics are involved in macrophage polarization by regulating a novel signaling network, involving the modulation from fusion (M2-TAMs) to mitochondrial fission (M1-TAMs). M2-TAMs targeting nanoparticles shMFN1-NPs were fabricated to deliver shMFN1 for repolarization of TAMs from the M2 to M1 phenotype by inhibiting mitochondrial fusion. Moreover, DOX-NPs effectively triggered the immunogenic cell death (ICD) of cancer cells, and the succeeding maturation of dendritic cells (DCs) promoted the infiltration and activation of CD8+T cells. MIX-NPs displayed the strongest antitumor efficacy (TIR = 83%) in the subcutaneous 4T1 tumor model. MIX-NPs suppressed the myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs) to further remodel the ITM. Taken together, our developed drug delivery strategy reversed the ITM and activated the antitumor immune response, providing a profound prospective treatment strategy in cancer immunotherapy.