The duplex stability with target mRNA and the gene silencing potential of a novel bridged nucleic acid analogue are described. The analogue,2′,4′-BNANCantisense oligonucleotides (AONs) ranging from 10- to 20-nt-long, targeted apolipoprotein B.2′,4′-BNANCwas directly compared to its conventional bridged (or locked) nucleic acid (2′,4′-BNA/LNA)-based counterparts. Melting temperatures of duplexes formed between2′,4′-BNANC-based antisense oligonucleotides and the target mRNA surpassed those of 2′,4′-BNA/LNA-based counterparts at all lengths. Anin vitrotransfection study revealed that when compared to the identical length2′,4′-BNA/LNA-based counterpart, the corresponding2′,4′-BNANC-based antisense oligonucleotide showed significantly stronger inhibitory activity. This inhibitory activity was more pronounced in shorter (13-, 14-, and 16-mer) oligonucleotides. On the other hand, the 2′,4′-BNANC-based 20-mer AON exhibited the highest affinity but the worstIC50value, indicating that very high affinity may undermine antisense potency. These results suggest that the potency of AONs requires a balance between reward term and penalty term. Balance of these two parameters would depend on affinity, length, and the specific chemistry of the AON, and fine-tuning of this balance could lead to improved potency. We demonstrate that2′,4′-BNANCmay be a better alternative to conventional2′,4′-BNA/LNA, even for “short” antisense oligonucleotides, which are attractive in terms of drug-likeness and cost-effective bulk production.