Photodynamic therapy (PDT) is a new therapeutic strategy for hypertrophic scars (HS), but it is limited by low drug utilization. Transdermal delivery based on nanoethosomes (ES) has attracted considerable attention as a potential clinical strategy in PDT treating HS. However, free ES are unsatisfactory due to their instability and non-targeting, which causes non-effective delivery and low drug utilization. Herein, 5-aminolevulinic acid (ALA)-loaded ES (ES-ALA) embedded in hyaluronic acid (HA) meshes (HA/ES-ALA), a novel synergistic transdermal delivery nanogel, are developed for enhancing PDT of HS. HA/ES-ALA has a unique structure and property to protect unilaminar ES-ALA with HA meshes and actively target hypertrophic scar fibroblasts (HSFs) with HA receptors. Bothin vitroandin vivoexperiments demonstrate that HA/ES-ALA has a remarkable transdermal delivery ability with penetrating channels and a membrane-fusion mechanism. Meanwhile, the synergistic delivery mechanism is visually characterized as three stages: synergistic penetration, targeting aggregation and transmembrane delivery. With the synergistic effect, HA/ES-ALA can realize a targeted transdermal delivery, and significantly improve ALA utilization and enhance PDT efficacy. The results demonstrate an effective transdermal delivery route to enhance therapy for HS as well as other skin diseases.