Spatiotemporally Controllable Covalent Bonding of RNA for Multi‐Protein Interference

Abstract

AbstractMany diseases are associated with genetic mutation and expression of mutated proteins, such as cancers. Therapeutic approaches that selectively target the synthesis process of multiple proteins show greater potential compared to single‐protein approaches in oncological diseases. However, conventional agents to regulate the synthesis of multiple protein still suffer from poor spatiotemporal selectivity and stability. Here, a new method using a dye‐peptide conjugate, PRFK, for multi‐protein interference with spatiotemporal selectivity and reliable stability, is reported. By using the peptide sequence that targets tumor cells, PRFK can be efficiently taken up, followed by specific binding to the KDELR (KDEL receptor) protein located in the endoplasmic reticulum (ER). The dye generates 1O2 under light irradiation, enabling photodynamic therapy. This process converts the furan group into a cytidine‐reactive intermediate, which covalently binds to mRNA, thereby blocking protein synthesis. Upon treating 4T1 cells, the proteomics data show alterations in apoptosis, ferroptosis, proliferation, migration, invasion, and immune infiltration, suggesting that multi‐protein interference leads to the disruption of cellular physiological activities, ultimately achieving tumor treatment. This study presents a multi‐protein interference probe with the potential for protein interference within various subcellular organelles in the future.