The pathogenesis and development of chronic obstructive pulmonary disease (COPD) are significantly related to cellular senescence. Strategies to eliminate senescent cells have been confirmed to benefit several senescence-related diseases. However, there are few reports of senolytic drugs in COPD management. In this study, we demonstrated elevated FOXO4 expression in cigarette smoke-induced senescent lung fibroblasts both in vitro and in vivo. Additionally, self-assembled DNA nanotubes loaded with single-stranded FOXO4 siRNA (siFOXO4-NT) were designed and synthesized to knockdown FOXO4 in senescent fibroblasts. We found that siFOXO4-NT can concentration- and time-dependently enter human lung fibroblasts (HFL-1 cells), thereby reducing FOXO4 levels in vitro. Most importantly, siFOXO4-NT selectively cleared senescent HFL-1 cells by reducing BCLXL expression and the BCL2/BAX ratio, which were increased in CSE-induced senescent HFL-1 cells. The findings from our work present a novel strategy for senolytic drug development for COPD therapy.
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