Cell‐Selective Delivery of RIBOTACs via an Anti‐EGFR Nanobody for Pancreatic Cancer Treatment

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge due to its dense stroma and lack of druggable targets. Through integrated bioinformatics analysis of in‐house and public datasets, we systematically identified miR‐21 as the most significantly upregulated oncomiR in PDAC, showing strong correlation with poor patient prognosis. RNA‐targeted degradation has emerged as a promising strategy for cancer treatment, enabling precise disruption of oncogenic signaling by degrading disease‐driving non‐coding RNAs. Nevertheless, poor tissue penetration and insufficient tumor specificity limit its therapeutic potential in pancreatic cancer, owing to the dense fibrotic stroma and heterogeneous target expression. Herein, we developed a dual‐targeting, bioresponsive Nb‐RIBOTAC (Nb‐Fc‐Val‐Cit‐RIBOTAC), engineered by conjugating a cathepsin B–responsive linker to bridge an EGFR‐targeting nanobody (Nb‐Fc fusion) with a miR‐21–specific RIBOTAC module. This rationally designed therapeutic achieved potent and selective miR‐21 degradation in orthotopic PDAC models, with 60% target knockdown while completely sparing normal tissues, leading to significant tumor growth inhibition. Our study establishes a transformative paradigm bridging bioinformatic identification with precision RNA degradation technology, offering new therapeutic possibilities for PDAC treatment. The target selection strategy and modular design principles described herein may be broadly applicable to other challenging malignancies.