Artificial Base-Directed In Vivo Assembly of an Albumin-siRNA Complex for Tumor-Targeting Delivery

RNA interference (RNAi) mediated by short interfering RNA (siRNA) is a promising method for cancer treatment, but the clinical application is hampered by several limitations, including metabolic instability, lack of tumor specificity, and poor cellular uptake. To meet these challenges, we have explored the possibility of structure modification of siRNA with artificial bases for property optimization. A series of siRNAs functionalized with different numbers of hydrophobic base F are prepared for screening. The interactions of plasma proteins with F -base-modified siRNA (F-siRNA) are investigated, and it is identified that the interaction with serum albumin is dominant. Experiments revealed that the introduction of F bases conferred modified siRNA with improved tumor-specific accumulation, prolonged circulatory retention time, and better tissue permeability. Mechanistic studies indicated that the F base induces the formulation of a stable siRNA-albumin complex, which transports siRNA tumor tissues selectively owing to an enhanced permeability and retention (EPR) effect of albumin. The F base also facilitates the binding of siRNA to transport-associated proteins on the cell membrane, enabling its cellular internalization. Together, these data demonstrate that F base modification confers siRNA-enhanced cellular uptake and biostability and specific accumulation in tumor tissue, which provides a new approach for the development of siRNA-based cancer therapeutics.

Automated summary

The modification of siRNA with artificial base F can improve its properties, such as tumor specificity and cellular uptake. The introduction of F base enables siRNA to interact with plasma proteins, especially serum albumin. Experimental results show that F base modification enhances the specific accumulation of siRNA in tumor tissue, prolongs its circulation time, and improves tissue permeability. Mechanistic studies reveal that the F base facilitates the formation of a stable siRNA-albumin complex, which is responsible for the selective delivery of siRNA to tumor tissues and its cellular internalization.