A photo-responsive, fisetin-functionalized DNA nanocage for programmed therapy to accelerate early-stage wound healing in aged skin

Age-related impaired wound healing presents distinct challenges compared to conventional wounds, primarily due to dysregulated phase kinetics of wound repair and chronic cellular senescence, which collectively disrupt the dynamic and orderly progression of tissue regeneration. Effective intervention requires a stage-specific and temporally programmed therapeutic strategy. To address this, we first performed transcriptome sequencing (RNA-seq) to elucidate the differential healing trajectory between young and aged wounds. Herein, we construct a photo-responsive, Fisetin-functionalized DNA nanocage (TAF) for spatiotemporally precise therapy of aged wounds. TAF is composed of a tetrahedral DNA nanocage loaded with a miR-29-targeting antisense oligonucleotide (ASO) covalently linked through a photocleavable linker and noncovalently encapsulating the senolytic agent Fisetin. The TAF platform enables a programmed therapeutic strategy: (a) the intrinsic antioxidant capacity of DNA scavenges excessive reactive oxygen species (ROS) during the early inflammatory phase; (b) photo-triggered ASO release in the proliferative phase promotes collagen synthesis; and (c) sustained Fisetin release eliminates senescent cells, fostering a pro-regenerative microenvironment. In vivo studies in aged mice reveal that TAF-mediated therapy significantly accelerates early wound closure and enhances high-quality tissue regeneration. In summary, TAF establishes an efficient nanomedicine platform that improves aged tissue repair through stage-specific, temporally programmed regulation.