Engineering nanoparticles boost TNBC therapy by CD24 blockade and mitochondrial dynamics regulation
Engineering nanoparticles boost TNBC therapy by CD24 blockade and mitochondrial dynamics regulation
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工程纳米粒子通过 CD24 阻断和线粒体动力学调节促进 TNBC 治疗
DOI：
10.1016/j.jconrel.2023.01.075
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发表时间：
2023
影响因子：
10.8
通讯作者：
Haiyang Hu
中科院分区：
文献类型：
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作者：
Ming Zhao;Ji Li;Fan Chen;Yanyan Han;Dawei Chen;Haiyang Hu
尽管肿瘤免疫治疗取得了显著进展，但三阴性乳腺癌（TNBC）的临床治疗仍坚韧取得突破。其治疗效果不理想可能与肿瘤免疫原性的缺乏和肿瘤微环境（ITM）的强烈免疫抑制有关。为了克服上述缺点，设计了工程纳米颗粒（P-aCD 24/CEL + P/shMFN 1）以递送抗CD 24单克隆抗体（aCD 24）、雷公藤红素（CEL）和丝裂融合蛋白1 shRNA（shMFN 1）用于协同肿瘤细胞靶向治疗和肿瘤相关巨噬细胞（TAM）靶向免疫调节。在肿瘤细胞上高度表达的CD 24与TAM上的Siglec 10相互作用以保护肿瘤细胞免受巨噬细胞的吞噬，因此已成为TNBC中的新的和主要的免疫检查点。P-aCD 24/CEL基于载体对肿瘤微环境中pH和MMP 2的双重响应实现了aCD 24的释放。此外，CEL增加“吃我”信号CRT并诱导肿瘤细胞的免疫原性细胞死亡（ICD），连同减少“不要吃我”信号CD 24，重新激活巨噬细胞对肿瘤细胞的吞噬作用，并最终改善基于巨噬细胞的免疫疗法。另一方面，P/shMFN 1可以靶向TAMs进行线粒体动力学调节，通过持续沉默TAMs中的MFN 1，从而逆转M2-TAMs的表型。P-aCD 24/CEL和P/shMFN 1可协同诱导明显的抗肿瘤免疫应答和长期免疫记忆，显著抑制肿瘤进展和术后复发。基于重塑ITM和增加抗肿瘤免疫应答，这种联合免疫治疗策略显示出治疗TNBC的巨大潜力。
Although cancer immunotherapy has achieved remarkable progress, the clinical treatment of triple-negative breast cancer (TNBC) is still tough to make a breakthrough. The unsatisfactory therapeutic effect may be attributed to the lack of tumor immunogenicity and the strong immunosuppressive tumor microenvironment (ITM). In order to overcome the above shortcomings, engineering nanoparticles (P-aCD24/CEL + P/shMFN1) was designed to deliver anti-CD24 monoclonal antibody (aCD24), celastrol (CEL) and mitofusin 1 shRNA (shMFN1) for synergistic tumor cells-targeted treatment and tumor-associated macrophages (TAMs)-targeted immunomodulation. CD24, highly expressed on tumor cells, interacts with Siglec10 on TAMs to protect tumor cells from phagocytosis by macrophages, and thus has become a novel and dominant immune checkpoint in TNBC. P-aCD24/CEL achieved the release of aCD24 based on the dual response of carrier to pH and MMP2 in tumor microenvironment. Moreover, CEL increased “eat me” signal CRT and induced the immunogenic cell death (ICD) of tumor cells, together with decreased “don't eat me” signal CD24, reactivated macrophage phagocytosis of tumor cells, and ultimately improves the macrophage-based immunotherapy. On the other hand, P/shMFN1 could target TAMs for mitochondrial dynamics regulationviadurable MFN1 silencing in TAMs, thereby reversing the phenotype of M2-TAMs. P-aCD24/CEL and P/shMFN1 could synergistically elicit evident antitumor immune responses and long-term immune memory to significantly inhibit tumor progress and postoperative recurrence. Based on remodeling the ITM and increasing antitumor immune response, this combination immunotherapy strategy showed great potential for TNBC treatment.