Co-delivery of doxorubicin and DNAzyme using ZnO@polydopamine core-shell nanocomposites for chemo/gene/photothermal therapy.

Multi-modal nanomedicines that synergistically combine chemo-, gene-, and photothermal therapy have shown great potential for cancer treatment. In this study, a core-shell nanosystem-based on a zinc oxide (ZnO) nanocore and a polydopamine (PDA) shell was constructed to integrate chemo- (doxorubicin, DOX), gene- (DNAzyme, DZ), and photothermal (PDA layer) therapy in one system. Instead of small interfering RNAs, we employed DZ for tumor-related gene (survivin) regulation owing to its higher stability, biocompatibility, and predictable activity. DOX and amino-modified DZ were loaded onto the PDA shell via physisorption and covalent conjugation, respectively. Specifically, the ZnO nanocore was designed as a metal cofactor reservoir to release Zn in response to intracellular stimuli, which triggered the activation of DZ for gene silencing after endocytosis into cells. Both in vitro and in vivo experiments demonstrated the enhanced anti-tumor efficacy of these multifunctional nanocomposites and highlighted the advantages of these nano-drug delivery systems to alleviate the side effects of DOX. This study provides a strategy for synergistic cancer therapy via chemo/gene/photothermal combination and offers a strategy to harness DZ as a gene-silencing tool for disease treatment in combination with other therapeutic modalities. STATEMENT OF SIGNIFICANCE: In this work, we constructed a core-shell nanosystem containing a zinc oxide (ZnO) nanocore and a polydopamine (PDA) outer layer, which integrated chemo- (doxorubicin, DOX), gene- (DNAzyme, DZ), and photothermal (PDA layer) therapies for multimodal cancer therapy. Specifically, the ZnO core was incorporated to solve the key issue of DZ for gene silencing applications, which acted as the metal cofactor reservoir to release Zn inside cells for effective DZ activation. In addition, the PDA shell could detoxify the ZnO by scavenging the reactive oxygen species produced by ZnO, thus increasing the biocompatibility of the nanocarrier. This work solves the key issue of DZ for RNAi-based applications, offers a platform to combine DZ with other therapeutic modalities, and also provides a smart strategy to achieve triggered activation of biocatalytic reactions for therapeutic applications.