Self‐assembled co‐delivery system of gold nanoparticles and paclitaxel based on in‐situ dynamic covalent chemistry for synergistic chemo‐photothermal therapy

Abstract Recently, stimuli‐responsive nanocarriers capable of precision drug release have garnered significant attention in the field of drug delivery. Here, an in‐situ dynamic covalent self‐assembled (DCS) strategy was utilized to develop a co‐delivery system. This assembly was based on a thiol‐disulfide‐exchange reaction, producing disulfide macrocycles in an oxidizing aerial environment. These macrocycles encapsulated the anti‐cancer drug (paclitaxel, PTX) on the surface of gold nanoparticles, which served as photothermal therapy agents during the self‐assembly. In the DCS process, the kinetic control over the concentration of each building unit within the reaction system led to the formation of a stable co‐delivery nanosystem with optimal drug‐loading efficiency. Notably, the high glutathione (GSH) concentrations in tumor cells caused the disulfide macrocycles in nanostructures to break, resulting in drug release. The stimuli‐responsive performances of the prepared nanosystems were determined by observing the molecular structures and drug release. The results revealed that the self‐assembled nanosystem exhibited GSH‐triggered drug release and good photothermal conversion capability under near‐infrared light. Moreover, the in vitro and in vivo results revealed that conjugating the targeting molecule of cRGD with co‐delivery nanosystem enhanced its biocompatibility, chemo‐photothermal anti‐cancer effect. Overall, our findings indicated that in‐situ DCS strategy enhanced the control over drug loading during the construction of the co‐delivery system, paving a way for the development of more functional carriers in nanomedicine.