CXCR4-Targeted Macrophage-Derived Biomimetic Hybrid Vesicle Nanoplatform for Enhanced Cancer Therapy through Codelivery of Manganese and Doxorubicin,ACS Applied Materials & Interfaces

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CXCR4-Targeted Macrophage-Derived Biomimetic Hybrid Vesicle Nanoplatform for Enhanced Cancer Therapy through Codelivery of Manganese and Doxorubicin
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2024-03-27 , DOI: 10.1021/acsami.3c18569
Yeonwoo Jang ₁ , Young Seok Cho _{2,

3} , April Kim ₂ , Xingwu Zhou ₂ , Yujin Kim _{2,

3} , Ziye Wan ₂ , James J Moon _{2,

3,

4} , Hansoo Park ₁

Affiliation

Immune-cell-derived membranes have garnered significant attention as innovative delivery modalities in cancer immunotherapy for their intrinsic immune-modulating functionalities and superior biocompatibilities. Integrating additional parental cell membranes or synthetic lipid vesicles into cellular vesicles can further potentiate their capacities to perform combinatorial pharmacological activities in activating antitumor immunity, thus providing insights into the potential of hybrid cellular vesicles as versatile delivery vehicles for cancer immunotherapy. Here, we have developed a macrophage-membrane-derived hybrid vesicle that has the dual functions of transporting immunotherapeutic drugs and shaping the polarization of tumor-associated macrophages for cancer immunotherapy. The platform combines M1 macrophage-membrane-derived vesicles with CXCR4-binding-peptide-conjugated liposomes loaded with manganese and doxorubicin. The hybrid nanovesicles exhibited remarkable macrophage-targeting capacity through the CXCR4-binding peptide, resulting in enhanced macrophage polarization to the antitumoral M1 phenotype characterized by proinflammatory cytokine release. The manganese/doxorubicin-loaded hybrid vesicles in the CXCR4-expressing tumor cells evoked potent cancer cytotoxicity, immunogenic cell death of tumor cells, and STING activation. Moreover, cotreatment with manganese and doxorubicin promoted dendritic cell maturation, enabling effective tumor growth inhibition. In murine models of CT26 colon carcinoma and 4T1 breast cancer, intravenous administration of the manganese/doxorubicin-loaded hybrid vesicles elicited robust tumor-suppressing activity at a low dosage without adverse systemic effects. Local administration of hybrid nanovesicles also induced an abscessive effect in a bilateral 4T1 tumor model. This study demonstrates a promising biomimetic manganese/doxorubicin-based hybrid nanovesicle platform for effective cancer immunotherapy tailored to the tumor microenvironment, which may offer an innovative approach to combinatorial immunotherapy.

中文翻译：

CXCR4靶向巨噬细胞衍生的仿生混合囊泡纳米平台，通过锰和阿霉素的共同递送增强癌症治疗

免疫细胞源性膜因其固有的免疫调节功能和卓越的生物相容性，作为癌症免疫治疗中的创新递送方式而受到广泛关注。将额外的亲本细胞膜或合成脂质囊泡整合到细胞囊泡中可以进一步增强它们在激活抗肿瘤免疫方面执行组合药理活性的能力，从而深入了解混合细胞囊泡作为癌症免疫治疗的多功能递送载体的潜力。在这里，我们开发了一种巨噬细胞膜衍生的混合囊泡，它具有运输免疫治疗药物和塑造肿瘤相关巨噬细胞极化以用于癌症免疫治疗的双重功能。该平台将 M1 巨噬细胞膜衍生的囊泡与载有锰和阿霉素的 CXCR4 结合肽缀合脂质体相结合。混合纳米囊泡通过 CXCR4 结合肽表现出显着的巨噬细胞靶向能力，从而增强巨噬细胞极化至以促炎细胞因子释放为特征的抗肿瘤 M1 表型。表达 CXCR4 的肿瘤细胞中负载锰/多柔比星的杂化囊泡可引发有效的癌症细胞毒性、肿瘤细胞的免疫原性细胞死亡和 STING 激活。此外，锰和阿霉素联合治疗促进树突状细胞成熟，从而有效抑制肿瘤生长。在 CT26 结肠癌和 4T1 乳腺癌小鼠模型中，静脉注射负载锰/阿霉素的混合囊泡，以低剂量即可产生强大的肿瘤抑制活性，且没有不良的全身影响。混合纳米囊泡的局部给药也在双侧 4T1 肿瘤模型中诱导脓肿效应。这项研究展示了一种有前途的仿生锰/阿霉素混合纳米囊泡平台，可用于针对肿瘤微环境的有效癌症免疫治疗，这可能为组合免疫治疗提供一种创新方法。

更新日期：2024-03-27

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