In this study, cyclodextrin-based nanostructures (CDNSs) were synthesized through the cross-linking of cyclodextrin (CD) with epichlorohydrin (ECH) as a cross-linker. Two types of CDNSs, α-CDNS and β-CDNS, were prepared to systematically investigate the influence of reaction parameters-such as the solubilization time of α-CD and β-CD, the molar ratio of ECH to CD, and NaOH concentration-on the physicochemical properties of the final product. Naproxen (NAP), a poorly water-soluble drug, was selected as a model compound to assess the drug-loading capacity of the synthesized CDNSs. The effect of each reaction parameter on NAP integration into the CDNSs was examined at varying weight ratios. The optimal reaction conditions were determined to be a solubilization time of 6 h, an ECH/CD molar ratio of 8/1, and an NaOH concentration of 33%. Under these conditions, the NAP loading efficiency of α-CDNSs was calculated as 67.12%. Comparative analysis revealed that α-CDNSs outperformed β-CDNSs in terms of drug-loading capacity. Additionally, the synthesized CDNSs and NAP-loaded CDNSs were characterized using FTIR, DSC, XRD, SEM, and Zetasizer analyses, while the NAP concentration was determined by HPLC.