Huang Hanji, Chen Yaoxuan, Li Lele, Zheng Li
Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application, Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, 530021, China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China.
Adv Mater. 2024 Dec;36(50):e2409035. doi: 10.1002/adma.202409035. Epub 2024 Oct 29.
Despite the significant potential of RNA-cleaving DNAzymes for gene regulation, their application is limited by low therapeutic efficacy and lack of cell-specific control. Here, a DNAzyme-based nanohybrid designed for ultrasound (US)-controlled, enzyme-activatable mRNA regulation is presented, enabling tumor cell-selective combination therapy. The nanohybrid is constructed by coordination-directed self-assembly of an enzymatically-triggerable therapeutic DNAzyme (En-Dz) and natural sonosensitizer hemoglobin (Hb). Controlled US exposure induces reactive oxygen species generation from Hb units, which not only facilitates efficient endosomal escape of En-Dz, but also promotes the translocation of specific enzyme from the nucleus to the cytoplasm, thereby enhancing gene regulation efficacy. Notably, the enzyme-triggered, spatiotemporally-controlled activation of En-Dz's catalytic activity results in enhanced cancer-cell selectivity in the therapeutic treatment. Furthermore, the combination of enzyme-activated mRNA regulation and sonodynamic therapy significantly enhances anti-tumor efficacy both in vitro and in vivo. This work highlights the potential of integrating a sonodynamic strategy to overcome the current limitations of DNAzyme-based gene regulators, providing a spatiotemporally-controlled approach for precise tumor treatment.
尽管RNA切割型脱氧核酶在基因调控方面具有巨大潜力，但其应用受到低治疗效果和缺乏细胞特异性控制的限制。在此，我们展示了一种基于脱氧核酶的纳米杂交体，其设计用于超声（US）控制的、酶激活的mRNA调控，从而实现肿瘤细胞选择性联合治疗。该纳米杂交体通过酶促触发的治疗性脱氧核酶（En-Dz）与天然声敏剂血红蛋白（Hb）的配位导向自组装构建而成。受控的超声暴露可诱导Hb单元产生活性氧，这不仅有助于En-Dz有效地从内体逃逸，还能促进特定酶从细胞核向细胞质的转运，从而提高基因调控效果。值得注意的是，酶触发的、时空控制的En-Dz催化活性激活导致治疗过程中癌细胞选择性增强。此外，酶激活的mRNA调控与声动力疗法的结合在体外和体内均显著提高了抗肿瘤疗效。这项工作突出了整合声动力策略以克服基于脱氧核酶的基因调节剂当前局限性的潜力，为精确肿瘤治疗提供了一种时空控制方法。
