Dual-engineered, "Trojanized" macrophages bio-modally eradicate tumors through biologically and photothermally deconstructing cancer cells in an on-demand, NIR-commanded, self-explosive manner.
Dual-engineered, "Trojanized" macrophages bio-modally eradicate tumors through biologically and photothermally deconstructing cancer cells in an on-demand, NIR-commanded, self-explosive manner.
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DOI：
10.1016/j.biomaterials.2020.120021
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发表时间：
2020-04
期刊：
影响因子：
14
通讯作者：
Lei Huang;Wenxi Yan;Bo Cai;Yu Song;Qiying Lv;Guobin Wang;Lin Wang;Zhenlian Wang
中科院分区：
文献类型：
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作者：
Lei Huang;Wenxi Yan;Bo Cai;Yu Song;Qiying Lv;Guobin Wang;Lin Wang;Zhenlian Wang
利用肿瘤细胞作为药物载体是提高肿瘤治疗特异性和有效性的一个很有前途的策略。然而，传统的基因工程细胞为基础的药物输送系统往往能够启动单一模式的治疗，并缺乏精确的时空控制释放的治疗有效载荷在肿瘤局部，因此可能会导致严重的全身毒性。在这里，巨噬细胞被遗传工程化以编码非分泌形式的EGFP-TNF α融合蛋白，并在细胞内携带近红外（NIR）响应性热纳米发生器（HIM）。由于巨噬细胞的内在肿瘤向性和HIM对NIR的光响应性，这些巨噬细胞（HIMs@eMET）可以在肿瘤部位主动积聚并经历由NIR诱导的HIM介导的光热效应（PTE）诱导的受控光热作用。这种热诱导的细胞爆炸使得非分泌型TNF α能够从巨噬细胞时空受控地释放，并有效地杀死癌细胞。重要的是，在临床前肿瘤模型中，HIMs@eMET主动迁移到肿瘤中，PTE和释放的EGFP-TNF α表现出增强的抗肿瘤作用，抑制肿瘤生长并显着延长动物生存期，而不会引起不良副作用。因此，这项研究证明了这种双重工程化巨噬细胞在双模式癌症治疗中的潜力。
To engineer tumor-tropic cells as drug delivery vehicles is a promising strategy to improve therapeutic specificity and efficacy for cancer treatment. However, conventional genetically engineered cell-based drug delivery systems are often capable of initiating single-mode therapy, and lack precise spatiotemporal control over the release of therapeutic payloads at tumor local, thus possibly causing severe systemic toxicity. Here, the macrophages are genetically engineered to encode a non-secreted form of EGFP-TNFα fusion protein and intracellularly carry near-infrared (NIR)-responsive heat-nanogenerators (HIMs). Owing to macrophages' intrinsic tumor tropism and HIMs’ photo-responsiveness to NIR, these macrophages (HIMs@eMET) can actively accumulate at tumor sites and undergo controlled photothermolysis induced by NIR-induced HIMs-mediated photothermal effects (PTE). Such heat-induced cell explosion enables spatiotemporally controlled release of non-secreted TNFα from macrophages and effectively kills cancer cells. Importantly, in a preclinical tumor model, HIMs@eMETactively migrate to tumors where PTE and released EGFP-TNFα exhibit an enhanced antitumor effect, suppressing tumor growth and significantly prolonging animal survival without eliciting adverse side effects. Thus, this study demonstrates the potential of such dual-engineered macrophages in bi-modal cancer therapy.