Huntington's disease (HD) is a progressive inherited neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene, which is translated into the pathologic mutant huntingtin (mHTT) protein. Despite the great potential of HTT lowering strategies and the numerous antisense oligonucleotides (ASOs) in pre- and clinical trials, sustained silencing of mHTT has not been achieved. As a strategy to improve ASO delivery, cyclodextrin-based nanoparticles (CDs) offer a promising approach. Here, three CDs with distinct chemical structures were designed and their efficacies were compared as potential platforms for the delivery of ASO targeting HTT. Results using striatal neurons and HD patient-derived fibroblasts indicate that modified ┐-CDs exhibited the best uptake efficiency and successfully downregulated mHTT at protein and allele levels. The incorporation of the brain-targeting peptide RVG into the modified ┐-CDs showed greater downregulation of mHTT protein and HD-causing allele SNP1 than untargeted ones in an in vitro blood-brain barrier model. Although the ASO sequence was designed as a nonallele-specific therapeutic approach, our strategy gives an additional benefit of some mHTT selectivity. Overall, this study demonstrated the CD platform's feasibility for delivering ASO-based therapeutics for HD treatment.