One of the major obstacles for nucleic acid-based medicine is cellular uptake due to the concern of efficiency and potential toxicity of the vehicle. In this work, we developed a novel approach to eliminate the need for a vehicle to allow for the cellular uptake of siRNA-based therapy with a unique modification strategy that also further enhances therapeutic efficacy. This discovery may be of great importance for the development of siRNA-based therapeutics as cellular uptake remains a critical challenge. In this study, we have tested the potential of this modification strategy for siRNA using a siRNA that targets B-cell lymphoma-2 (BCL-2). BCL-2 is an important anti-apoptotic gene and is overexpressed in many different cancers. As a result, venetoclax, a BCL-2 inhibitor, has been developed and is currently used either alone or in combination with obinutuzumab (Gazyva) or rituximab (Rituxan) to treat certain types of chronic lymphocytic leukemia (CLL) or certain types of small lymphocytic lymphoma (SLL). It is also used in combination with either azacitidine (Vidaza), decitabine (Dacogen), or cytarabine as a treatment for acute myeloid leukemia (AML). In this study, we generated a modified siRNA against BCL-2 in which all uracil residues in the sense and antisense strands are replaced with 5-fluorouracil (5-FU). 5-FU is a uracil analog that blocks de novo pyrimidine biosynthesis by forming a suicide complex with its target protein thymidylate synthase (TYMS, TS) and its metabolite, fluorodeoxyuridine monophosphate (FdUMP). Based on this, 5-FU is one of the major chemotherapeutic agents used to treat various tumor types.