Abstract: Objective To screen aptamers that specifically bind to cisplatin-resistant A549/DDP lung cancer cells and evaluate their potential in targeted drug delivery systems. Methods Aptamers were screened through Systematic Evolution of Ligands by Exponential Enrichment (Cell SELEX), and the binding capacity of different pools of single-stranded DNA (ssDNA) with A549/DDP cells was assessed by Enzyme-Linked Oligonucleotide Assay (ELONA). The aptamers with the strongest binding were selected, and their sequences were obtained by PCR amplification and enzyme digestion. Flow cytometry was used to verify the binding ability of the aptamers. Curcumin-loaded aptamer-targeted zinc nanocapsules were then constructed and their targeting and drug delivery effects were evaluated. Results ELONA results showed that there was no significant difference in binding strength between the 11th and 12th pools. Aptamer A5 exhibited the strongest binding affinity, with a dissociation constant (Kd) of (37.10±9.29) nmol/L. Flow cytometry further confirmed the dose-dependent binding of A5 to A549/DDP cells. Curcumin-loaded zinc nanocapsules targeted by aptamer A5 specifically bound to A549/DDP cells and enhanced cisplatin (DDP)-induced apoptosis. Conclusions The selected aptamer A5 effectively targets A549/DDP cells and combines with zinc nanocarriers, providing a novel therapeutic strategy for resistant tumors.