Mitochondria-targeted liposome-enveloped covalent organic framework co-delivery system for enhanced tumor therapy

Mitochondria-targeted therapeutic strategies are widely used in the targeted delivery of anti-tumor drugs to achieve effective and precise treatment. Herein, a pH-responsive and mitochondria-targeted liposome-enveloped methoxylated covalent organic framework (mCOF) delivery system loaded with doxorubicin (DOX) and camp-tothecin (CPT) is constructed. Different from introducing additional mitochondria-targeting molecules, we incorporate amphiphilic DOX-lipid molecules into a lipid bilayer to achieve mitochondria-targeted and thera-peutic agent delivery (DOX) to induce oxidative stress in tumor mitochondria. Furthermore, CPT, which can also induce mitochondrial oxidative stress, is co-loaded with DOX-lipid using mCOF with high porosity to enhance the synergistic therapeutic effects. In addition, cholesteryl hemisuccinate is assembled with amphiphilic DOX-lipid on the surface of the mCOF to achieve pH-sensitive drug release. Consequently, the DOX-CPT dual drug -loaded delivery system with mitochondria-targeted ability can efficiently increase the level of reactive oxygen species in the mitochondria and enhance anti-tumor efficacy compared with other groups. Given its good biocompatibility, the constructed dual drug delivery platform based on liposome-enveloped mCOF synergisti-cally combines mitochondria-targeted DOX-lipid with mitochondria-acted CPT, which provides a feasible strategy for organelle-targeted combination chemotherapy to improve therapeutic effects.