NGR‐Modified CAF‐Derived exos Targeting Tumor Vasculature to Induce Ferroptosis and Overcome Chemoresistance in Osteosarcoma

Abstract Osteosarcoma (OS) chemoresistance presents a significant clinical challenge. This study aims to investigate the potential of using tumor vascular‐targeting peptide NGR‐modified cancer‐associated fibroblasts (CAFs)‐derived exosomes (exos) to deliver circ_0004872‐encoded small peptides promoting autophagy‐dependent ferroptosis to reverse chemoresistance in OS. Through combined single‐cell transcriptome analysis and high‐throughput sequencing, it identified circ_0004872 associated with chemoresistance. Subsequent experiments demonstrated that the small peptide encoded by this Circular RNA (circRNA) can effectively reverse chemoresistance by enhancing OS cell sensitivity to chemotherapy via the mechanism of promoting autophagy‐dependent ferroptosis. Moreover, in vitro and in vivo results confirmed the efficient delivery of NGR‐modified CAFs‐derived exo‐packaged circ_0004872‐109aa to tumor cells, thereby improving targeted therapy efficacy. This study not only offers a novel strategy to overcome chemoresistance in OS but also highlights the potential application value of utilizing exos for drug delivery.