PDF(Pubmed)
Abstract：
Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO2(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms.
摘要：
化学抗性仍然是导致癌症复发的有效乳腺癌治疗的重大挑战。CRISPR指导的基因编辑成为通过重新编程肿瘤微环境来减少化学耐药性的强大工具。先前的研究表明，中草药提取物具有克服肿瘤化疗耐药性的巨大潜力。然而,由于其较差的肿瘤靶向性和体内耐久性,治疗效果通常是有限的。在这里，我们开发了一种肿瘤微环境响应性纳米平台（H-MnO2（ISLDOX）-PTPN2@HA，M（ID）PH）用于纳米草药和CRISPR共递送以降低化学抗性。通过异甘草素（ISL）与多柔比星（DOX）的治疗实现了协同肿瘤抑制作用，通过基于CRISPR的基因编辑增强，靶向蛋白酪氨酸磷酸酶非受体2型（PTPN2）以启动长期免疫疗法。用M(I+D)PH纳米颗粒处理后观察到有效的PTPN2消耗，这导致肿瘤组织中浸润淋巴细胞的募集和促炎细胞因子的增加。总的来说,我们的纳米颗粒平台为实现协同化疗和免疫疗法提供了多种技术，它为恶性肿瘤提供了有效的治疗选择。
