Hypertrophic scar (HS), which results from prolonged inflammation and excessive fibrosis in re-epithelialized wounds, is one of the most common clinical challenges. Consequently, sophisticated transdermal transfersome nanogels (TA/Fu-TS) are prepared to control HS formation by synergistically inhibiting inflammation and suppressing fibrosis. TA/Fu-TSs have unique structures comprising hydrophobic triamcinolone acetonide (TA) in lipid multilayers and hydrophilic 5-fluorouracil in aqueous cores, and perform satisfactorily with regard to transdermal co-delivery to macrophages and HS fibroblasts in emerging HS tissues. According to the in vitro/vivo results, TA/Fu-TSs not only promote macrophage phenotype-switching to inhibit inflammation by interleukin-related pathways, but also suppress fibrosis to remodel extracellular matrix by collagen-related pathways. Therefore, TA/Fu-TSs overcome prolonged inflammation and excessive fibrosis in emerging HS tissues, and provide an effective therapeutic strategy for controlling HS formation via their synergy of macrophage phenotype-switching and anti-fibrosis effect. Transfersome nanogels (TA/Fu-TS) realize the transdermal co-delivery of hydrophobic triamcinolone acetonide and hydrophilic 5-fluorouracil to macrophages and fibroblasts in emerging hypertrophic scars (HS). Then, TA/Fu-TSs promote macrophage phenotype-switching to inhibit inflammation and suppress fibrosis to remodel extracellular matrix. Therefore, TA/Fu-TSs overcome prolonged inflammation and excessive fibrosis in emerging HS tissues, and provide an effective strategy for controlling HS formation.image