Stimulated Raman Scattering to track the delivery of ASO and/or TPD into cells and tissues

反义寡核苷酸(ASO)是一种新的治疗方式，迅速获得了吸引力，目前约有120种ASO处于临床试验中，6种药物已被批准上市。ASO是一种短的、人工合成的、经过化学修饰的寡核苷酸，它与靶RNA的互补序列结合，导致其降解或剪接过程的改变。尽管它们在临床上取得了显著的成功，但细胞摄取ASO的内吞机制仍然知之甚少，从而限制了ASO的疗效。因此，提高我们对ASO是如何在细胞和组织中被摄取和分布的理解将有助于加速这一领域的药物发现。第二种新出现的治疗策略是通过劫持细胞内的蛋白分解机制来诱导细胞靶标的靶向蛋白降解(TPD)。本研究的目的是基于受激拉曼散射(SRS)显微镜的最新创新，开发一种在亚细胞分辨率下高灵敏度和高特异性地跟踪ASO和/或TPD治疗药物在细胞和组织中的传递和分布的方法。

Antisense oligonucleotides (ASOs) are a new therapeutic modality that have rapidly gained traction, with about 120 ASOs currently in clinical trials and 6 approved drugs on the market. ASOs are short, synthetic, chemically modified oligonucleotides that bind to the complementary sequence of the target RNA, inducing its degradation or alteration of splicing process. Despite their phenomenal success in the clinic, the endocytic mechanisms of ASO uptake by cells are still poorly understood thus limiting ASO efficacy. Therefore, improving our understanding of how ASOs are taken up and distributed in cells and tissues would help accelerate drug discovery in this field. A second emerging therapeutic strategy is the induction of Targeted Protein Degradation (TPD) of cellular targets by hijacking the intracellular proteolysis machinery. The aim of this study is to develop a method to track the delivery and distribution of ASO and/or TPD therapeutics in cells and tissues with high sensitivity and specificity at subcellular resolution based on the newest innovations in Stimulated Raman Scattering (SRS) microscopy.