The structure-guided design of RNA aptamers targeting membrane proteins represents a growing opportunity, particularly given the therapeutic potential of nucleic acid therapeutics and the prevalence of G protein-coupled receptors (GPCRs) as drug targets. Here, we report an integrated computational and experimental approach to prioritize and structurally characterize a 45-nucleotide RNA aptamer (Apt-MC1R-1) targeting the melanocortin-1 receptor (MC1R), a therapeutically relevant GPCR overexpressed in melanoma. Our strategy combined RNA secondary- and tertiary-structure prediction, molecular docking, and molecular dynamics simulations to identify candidate sequences systematically. Apt-MC1R-1 was predicted to adopt a stable stem-loop conformation compatible with MC1R extracellular domains and to form persistent intermolecular contacts during 150 ns simulations. The modeled complex exhibited sustained hydrogen bonding and reduced solvent-accessible surface area, consistent with stable interface formation. Circular dichroism spectroscopy confirmed that the synthesized aptamer adopts a stable RNA secondary structure consistent with computational predictions. For functional evaluation, a chemically modified aptamer (Cy5.5-labeled, cholesterol-conjugated, 2'-O-methyl-modified) was presented on exosome surfaces (Apt-Exo) and analyzed by flow cytometry. Apt-Exo demonstrated preferential cellular association with MC1R-expressing WM164 melanoma cells compared to MC1R-negative HEK293T cells, achieving a selectivity index of 5.4. α-Melanocyte-stimulating hormone (α-MSH, ∼14 μM) did not reduce association and increased the selectivity index to 6.9, consistent with non-competitive interaction behavior under the tested conditions. These findings support the feasibility of a structure-guided computational framework for aptamer prioritization and provide a foundation for the development of aptamer-based targeted delivery strategies.