Kinetic control over co-self-assembly using an in situ dynamic covalent reaction resulting in a synergistic chemo-photodynamic therapy

Abstract

Multicomponent self-assembly offers a strategy to explore ordered, complex, and dynamic nanosystems and to harness the property of the whole system beyond that of each subcomponent. However, the spontaneous nature of co-self-assembly makes control of the process difficult. Here, we use a thiol-disulfide exchange reaction as an in situ dynamic covalent reaction to slowly produce disulfide macrocycles that subsequently trigger the co-self-assembly with an anticancer drug and a photosensitizer. The gradual concentration growth of products shows kinetic control over the concentration of self-assembling disulfides, resulting in a stable co-delivery nanosystem with high drug-loading efficiency (31.78%) and encapsulation efficiency (95.91%). The nanosystem possesses biocompatibility, tumor-accumulating ability, and biosafety and shows a synergistic chemotherapeutic and photodynamic anticancer effect in vitro and in vivo. Our findings suggest that in situ dynamic covalent chemistry advances control over co-self-assembly, paving the way to more functional nanosystems with potential applications in biomedicine, electronics, and renewable energy.