Abstract：
Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.
摘要：
如今,针对三阴性乳腺癌(TNBC)的有效免疫疗法由于具有免疫抑制性的肿瘤微环境而仍然具有挑战性.免疫检查点抑制剂主要用于恢复肿瘤特异性免疫细胞的活性，然而，由于肿瘤浸润性CD8+T细胞的数量有限和免疫药物向肿瘤组织的低效递送，其治疗效果甚微。为了解决这些问题,我们在此构建了一个定制的溶解微针共封装TLR7/8激动剂R848和免疫检查点抑制剂aPD-1，称为αNP-RNP@DMN，并将其制造为透皮给药系统。这个精心设计的微针贴片，具有高效的肿瘤给药能力，能够成熟肿瘤浸润的树突状细胞（TIDC），并在R848的帮助下进一步促进CD8T细胞向肿瘤组织的浸润。此外，aPD-1的引入阻断了程序性细胞死亡蛋白1/程序性细胞死亡配体1（PD-1/PD-L1）免疫检查点，协同逆转TNBC的免疫抑制微环境。体内治疗结果表明,αNP-RNP@DMN不仅显著延长了4T1荷瘤小鼠的生存时间,还能抑制肿瘤术后复发和肺转移,这意味着这种有效的药物递送系统在增强浅表肿瘤的免疫治疗中的巨大潜力。重要声明：有限数量的肿瘤浸润性CD8+T细胞和免疫药物向肿瘤组织的低效递送阻碍了三阴性乳腺癌（TNBC）的有效免疫治疗。在这里，开发并制造了共封装TLR7/8激动剂R848和免疫检查点抑制剂aPD-1的溶解微针作为透皮给药系统.这种量身定制的微针贴片不仅以安全无痛的方式促进了药物在肿瘤部位的积累，但也解除了肿瘤浸润性树突状细胞（TIDC）的免疫抑制状态。活化的TIDC进一步增强了T细胞向肿瘤组织的浸润,从而成功地提高了aPD-1的疗效。这项研究表明，这种精心设计的微针贴片可以作为一种有效的药物递送系统，用于增强TNBC的免疫治疗。
