School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, P. R. China.
Sci Adv. 2023 Sep 29;9(39):eadi1965. doi: 10.1126/sciadv.adi1965. Epub 2023 Sep 27.
Precise killing of tumor cells without affecting surrounding normal cells is a challenge. Mitochondrial DNA (mtDNA) mutations, a common genetic variant in cancer, can directly affect metabolic homeostasis, serving as an ideal regulatory switch for precise tumor therapy. Here, we designed a mutation-induced drug release system (MIDRS), using the single-nucleotide variation (SNV) recognition ability and trans-cleavage activity of Cas12a to convert tumor-specific mtDNA mutations into a regulatory switch for intracellular drug release, realizing precise tumor cell killing. Using Ce6 as a model drug, MIDRS enabled organelle-level photodynamic therapy, triggering innate and adaptive immunity simultaneously. In vivo evaluation showed that MIDRS could identify tumor tissue carrying SNVs in mtDNA in unilateral, bilateral, and heterogeneous tumor models, producing an excellent antitumor effect (~82.6%) without affecting normal cells and thus resulting in a stronger systemic antitumor immune response. Additionally, MIDRS was suitable for genotype-specific precision drug release of chemotherapeutic drugs. This strategy holds promise for mutation-specific personalized tumor treatment approaches.
精准杀死肿瘤细胞而不影响周围正常细胞是一项挑战。线粒体 DNA（mtDNA）突变是癌症中一种常见的遗传变异，它可以直接影响代谢稳态，是精确肿瘤治疗的理想调控开关。在这里，我们设计了一种突变诱导药物释放系统（MIDRS），利用 Cas12a 的单核苷酸变异（SNV）识别能力和转录切割活性，将肿瘤特异性 mtDNA 突变转化为细胞内药物释放的调控开关，实现对肿瘤细胞的精准杀伤。以 Ce6 作为模型药物，MIDRS 能够进行细胞器水平的光动力治疗，同时触发固有和适应性免疫。体内评价表明，MIDRS 能够在单侧、双侧和异质性肿瘤模型中识别携带 mtDNA SNV 的肿瘤组织，产生优异的抗肿瘤效果（~82.6%），而不影响正常细胞，从而引发更强的全身抗肿瘤免疫反应。此外，MIDRS 适用于基于基因型的化疗药物的特异性精准药物释放。该策略有望为基于突变的个性化肿瘤治疗方法提供新的思路。
