Targeted Therapy of Oral Squamous Cell Carcinoma with Cancer Cell Membrane Coated Co‐Fc Nanoparticles Via Autophagy Inhibition

Abstract Systemic chemotherapy for oral squamous cell carcinoma (OSCC) is associated with multidrug resistance and systemic adverse effects. Cobalt‐ferrocene metal–organic framework (Co‐Fc) is a nanoparticle synthetized by ferrocene and cobalt with a stronger Fenton reaction that can locally generate hydroxyl radical and effectively kill tumors. However, tumor cells can remove exogenous substances through autophagy activity to maintain the internal environment homeostasis. Herein, Co‐Fc loaded with the classical autophagy inhibitor hydroxychloroquine (HCQ) to construct Co‐Fc@HCQ nanoparticles is synthetized. The ferrocene in Co‐Fc catalyzes the production of endogenous reactive oxygen species (ROS) through the Fenton reaction. The presence of HCQ inhibits the fusion of autophagy vesicles with lysosomes and reduces the scavenging of ROS. In addition, to enhance the tumor targeting effect of Co‐Fc@HCQ nanoparticles, oral cancer cell membranes (CM) are extracted from CAL‐27 cell line to construct CM@Co‐Fc@HCQ nanoparticles with good homologous targeting and immune escape effects. The results prove the good tumor targeting, biosafety as well as the therapeutic effect of CM@Co‐Fc@HCQ. In conclusion, via specific tumor targeting and local autophagy‐conducted ROS boosting, CM@Co‐Fc@HCQ nanoparticles, a smart local delivery chemo‐dynamic substance, provide a promising approach for effectively treating OSCC.