RNA interference (RNAi) is an endogenous pathway that uses double-stranded RNA to suppress the expression of a target mRNA, resulting in sequence-specific gene silencing. Delivering siRNA to target cells or tissues has been one of the major challenges in RNAi research. Due to their large size and polyanionic backbone, bare siRNAs cannot diffuse across cell membranes. Therefore, receptor-targeted ligands can be used to deliver siRNAs to target cells and tissues. For example, vitamin folic acid, which has been widely used as a drug delivery system to target folate receptors (FRs) in tumor cells, is a cell surface glycoprotein that binds folate with high affinity. These receptors are expressed at low levels in most tissues because their expression is restricted to cells important for folate uptake and embryonic development, but they are highly overexpressed on the surface of many cancers. This includes about 90% of ovarian cancers as well as breast, endometrial, brain and kidney cancers. Once bound to FR, folate enters the cell via receptor-mediated endocytosis. Remarkably, folate binding retains the ability to bind to and be internalized by this receptor, making FR an attractive molecular target for cancer research.
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Folic acid conjugates leverage high-affinity binding to folate receptors overexpressed on specific cell types, enabling receptor-mediated endocytosis for precise cellular uptake and reduced off-target effects.
Cells with elevated folate receptor expression, including various research cell lines derived from epithelial tissues, are ideal candidates for this targeted delivery approach.
Strategic conjugation chemistry preserves siRNA structural integrity and silencing activity while ensuring efficient folic acid receptor binding and intracellular release.
Yes, additional modifications including stability enhancers, fluorescent tags, and secondary targeting ligands can be incorporated to create multifunctional conjugates for complex research applications.
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