Pancreatic Ductal Adenocarcinoma (PDAC) accounts for almost half a million deaths globally. The global incidence and mortality rates are similar, meaning almost every individual diagnosed with PDAC has a slim chance of survival. These statistics result from ineffective treatments, highlighting the urgent need for further research. That's why we invented CLOTHO, a modular gene therapy approach for curing PDAC. We used an adeno-associated virus to deliver a therapeutic transgene, via an injection, that activates only in cancerous cells. Once inside, the construct produces two key components: circular RNAs and an enzyme. The circular RNAs sponge up tumor-promoting miRNAs, making cancer cells more responsive to chemotherapy. The enzyme then activates a harmless prodrug 5-fluorocytosine into its toxic agent 5-fluorouracil, causing targeted destruction. We, also, developed a software platform that generates custom circular RNA sequences tailored to each patient’s genetic profile. With our approach we aim to minimize off-target effects and ensure precision, while introducing an innovative way to tackle drug resistance in cancer and other diseases.