Bioorthogonal CRISPR/Cas9-Drug Conjugate: A Combinatorial Nanomedicine Platform

Bioconjugation of proteins can substantially expand the opportunities in biopharmaceutical development, however, applications are limited for the gene editing machinery despite its tremendous therapeutic potential. Here, a self-delivered nanomedicine platform based on bioorthogonal CRISPR/Cas9 conjugates, which can be armed with a chemotherapeutic drug for combinatorial therapy is introduced. It is demonstrated that multi-functionalized Cas9 with a drug and polymer can form self-condensed nanocomplexes, and induce significant gene editing upon delivery while avoiding the use of a conventional carrier formulation. It is shown that the nanomedicine platform can be applied for combinatorial therapy by incorporating the anti-cancer drug olaparib and targeting the RAD52 gene, leading to significant anti-tumor effects in BRCA-mutant cancer. The current development provides a versatile nanomedicine platform for combination treatment of human diseases such as cancer.

Automated summary

Bioconjugation of proteins offers great potential in biopharmaceutical development, but the application of gene editing machinery is still limited. In this study, a self-delivered nanomedicine platform based on bioorthogonal CRISPR/Cas9 conjugates is introduced, which can be armed with a chemotherapeutic drug to achieve combinatorial therapy. The results show that multi-functionalized Cas9 can form self-condensed nanocomplexes with a drug and polymer, leading to significant gene editing without the need for conventional carrier formulations. The platform is demonstrated to be applicable for combinatorial therapy by incorporating the anti-cancer drug olaparib and targeting the RAD52 gene, resulting in significant anti-tumor effects in BRCA-mutant cancer. This development provides a versatile nanomedicine platform for combination treatment of human diseases such as cancer.