Supramolecular Drug–Drug Complex Vesicles Enable Sequential Drug Release for Enhanced Combination Therapy

Drug–drug self-delivery systems serving as both carriers and cargos have been explored as advanced combination chemotherapy strategies to overcome the limitations of the traditional single-drug chemotherapy. However, most known drug–drug self-delivery systems may cause a rapid increase in drug concentration when the single covalent bond is broken, thus leading to high toxicity to organs and low therapeutic efficiency against tumors. To address the above problem, in this study, a novel supramolecular drug–drug complex (SDDC) simultaneously containing both covalent and noncovalent bonds was proposed to realize the sequential release of two drugs in tumor cells for enhanced combination therapy. The SDDC could self-assemble into uniform bilayer supramolecular vesicles (SVs) with a remarkable drug loading capacity and stable drug transport. Notably, the SVs with controlled sequential release ability in tumor cells exhibited a superior synergistic effect and significantly improved therapeutic efficiency with reduced toxicity in in vivo antitumor activity and histological analyses in comparison to either individual free drugs or a mixture of two free drugs. Therefore, by combining the advantages of noncovalent interactions with the dynamic nature and stable covalent bonds, this study opens a new way for cancer therapy.