A Mitochondria‐Targeted Biomimetic Nanomedicine Capable of Reversing Drug Resistance in Colorectal Cancer Through Mitochondrial Dysfunction

Abstract Chemoresistance and metastasis are the main obstacles to the clinical success of anticancer treatment and are responsible for most cancer deaths. Developing effective approaches to reverse chemoresistance and inhibit metastasis is essential for efficient chemotherapy. Mitochondria are important sources of cellular energy and are involved in mediating chemoresistance and driving tumor metastasis. Due to the relatively weak DNA repair capacity of mitochondria, targeting mitochondria may reverse chemoresistance and provide a paradigm for metastatic cancer treatment. Herein, exosomes (Exos) modified with integrin ligands and mitochondriotropic molecules are synthesized for encapsulating oxaliplatin (OXA) to construct a sequentially targeted and mitochondrion‐dysfunctional nanodrug (OXA@Exo‐RD). Subsequent investigations confirm that OXA@Exo‐RD targeted cancer cells and mitochondria in sequence, and OXA delivered to mitochondria lacking DNA repair mechanisms reduce the likelihood of deactivation. Furthermore, the OXA@Exo‐RD promotes the overproduction of ROS, inhibited ATP generation, and induces mitochondria‐mediated apoptosis and mitochondrial dysregulation. Finally, OXA@Exo‐RD shows the potential to inhibit the growth and metastasis of HCT116/OXA cells in vitro, which is further validated in subcutaneous and orthotopic CRC models, as well as in CRC metastasis models. Taken together, this dual‐targeting nanomedicine induces apoptosis via mitochondrial signaling pathways, providing an attractive strategy for the treatment of drug‐resistant CRC.