Oligonucleotide (ON) therapeutics are emerging as a new generation of medicine with tremendous potential, but their clinical translation is hampered by inferior stability and short circulation time in the human body. Here, we report a general approach to manipulating the interaction between ONs and albumin by modulating hydrophobicity. A series of DNA aptamer derivatives were designed and prepared by programmable synthesis as an ON library with a gradient of hydrophobic base ‘F’. In vitro experiments revealed that the introduction of two F bases at both ends of ONs enhanced the biostability without sacrificing biological activities, while the binding affinity toward albumin was dramatically increased with Kd in the range of 100 nM to 1 μM. In vivo imaging confirmed the immediate formation of the aptamer–albumin complex after the injection, and the circulation time of the aptamer was dramatically elongated owing to the enhanced biostability and retarded renal excretion. The programmable incorporation of the F base provides a general approach to regulating albumin-binding affinity and enhancing the stability of aptamers in vivo, conferring aptamer therapeutics prolonged circulation time to meet clinical requirements.

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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 Fbase-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 to 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.