Precise Delivery of Nanomedicines to M2 Macrophages by Combining “Eat Me/Don't Eat Me” Signals and Its Anticancer Application
Precise Delivery of Nanomedicines to M2 Macrophages by Combining “Eat Me/Don't Eat Me” Signals and Its Anticancer Application
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结合“吃我/别吃我”信号将纳米药物精确递送至 M2 巨噬细胞及其抗癌应用
DOI：
10.1021/acsnano.1c06707
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发表时间：
2021
期刊：
影响因子：
17.1
通讯作者：
Chong Li
中科院分区：
文献类型：
--
作者：
Yixuan Tang;Zhongjie Tang;Pingrong Li;Kaicheng Tang;Zhongyi Ma;Yantong Wang;Xiaoyou Wang;Chong Li
已提出将纳米药物靶向递送至M2肿瘤相关巨噬细胞（TAMs），以减少肿瘤促进并增强抗癌治疗的功效。然而，M2 TAM上上调的受体也在M1 TAM和正常组织中的其它巨噬细胞上表达。因此，提高靶向特异性仍然是一个关键挑战。在这里，我们开发了一种精确的M2 TAM靶向输送系统，使用“吃我”和“不吃我”信号。在脂质体上引入CD 47衍生的自身肽配体（不要吃我信号）和半乳糖配体（吃我信号）。可切割的磷脂-聚乙二醇覆盖在表面，并能与自身肽联合收割机结合，即使在免疫球蛋白M吸附后也能抑制巨噬细胞识别，并保护半乳糖免于肝脏清除，从而延长循环时间，促进脂质体在肿瘤中的积聚。这种可分离的聚合物可以在通过肿瘤内皮细胞转胞吞作用时被氧化还原微环境去除，并重新暴露自身肽和半乳糖。自身肽高度降低M1巨噬细胞吞噬作用，半乳糖配体增强脂质体和M2巨噬细胞之间的相互作用。因此，修饰的脂质体能够特异性识别M1/M2 TAM。体外证据显示M1巨噬细胞对脂质体的内吞作用降低。此外，体内研究表明，阿霉素负载的脂质体有效地消除了M2 TAM，但不影响M1 TAM，增强了抗肿瘤治疗的效力。总的来说，我们的研究结果表明，结合主动逃逸和主动靶向精确地将感兴趣的药物递送到M2巨噬细胞的潜力，并表明其在抗癌治疗中的应用。
Targeted delivery of nanomedicines to M2 tumor-associated macrophages (TAMs) has been proposed to reduce tumor promotion and enhance the efficacy of anticancer therapy. However, upregulated receptors on M2 TAMs are also expressed on M1 TAMs and other macrophages in normal tissues. Therefore, improving targeting specificity remains a key challenge. Here, we developed a precise M2 TAM-targeted delivery system using "eat-me" and "don't-eat-me" signals. A CD47-derived self-peptide ligand (don’t-eat-me signal) and galactose ligand (eat-me signal) were introduced on liposomes. Cleavable phospholipid-polyethylene glycol was covered on the surface and could combine with the self-peptide to inhibit macrophage recognition even after immunoglobulin M adsorption and protect galactose from hepatic clearance to prolong the circulation time and promote the accumulation of liposomes in tumors. This detachable polymer can be removed by the redox microenvironment upon transcytosis through the tumor endothelium and re-expose the self-peptide and galactose. The self-peptide highly reduced M1 macrophage phagocytosis, and the galactose ligand enhanced the interaction between the liposomes and M2 macrophages. Thus, the modified liposomes enabled specific recognition of M1/M2 TAMs. In vitro evidence revealed reduced endocytosis of the liposomes by M1 macrophages. Moreover, in vivo studies demonstrated that doxorubicin-loaded liposomes efficiently eliminated M2 TAMs but did not affect M1 TAMs, enhancing the potency of the anti-tumor therapy. Collectively, our results demonstrate the potential of combining active escape and active targeting for precisely delivering a drug of interest to M2 macrophages and suggest its application in anticancer therapy.