Skin aging exacerbates chronic skin diseases, malignancies, and systemic aging. During the aging process, ultraviolet radiation induces oxidative stress, DNA damage, and senescence, resulting in dermal extracellular matrix (ECM) microenvironmental dysregulation. Based on this, reshaping strategies aiming at the dermal ECM microenvironment should center on two key mechanisms: (1) remodel the ECM microenvironment by removing senescent cells (SenCs); (2) restore the epidermal barrier function to maintain the homeostasis of the dermal ECM microenvironment. To achieve dual-action therapy, we propose a hybrid hydrogel microneedle system (SC/F-HMNs) that synergizes fisetin-loaded nanoparticles with recombinant human collagen XVII (rhCol17)-reinforced silk fibroin hydrogel. The SC/F-HMNs exhibited superior mechanical strength and sustained drug release, enabling deep dermal penetration. In UVA-irradiated human skin fibroblasts (HSFs), the SC/F hydrogel enhanced cell viability and migration capacity and promoted ECM remodeling, significantly reducing levels of reactive oxygen species (ROS) and DNA damage, and attenuating senescence. In UVA-irradiated photoaged mice, SC/F-HMNs treatment exhibited improvement in skin wrinkles and elasticity. Additionally, in vivo studies demonstrated that SC/F-HMNs decreased oxidative stress, DNA damage, and restored barrier function, effectively reshaping the dermal ECM environment, including the collagen and elastic pattern, as well as MMP1,3 expression. Our data demonstrate the therapeutic potential of SC/F-HMNs in reshaping the dermal microenvironmental dysregulation caused by oxidative stress in photoaging, thereby providing an innovative therapeutic strategy for treating skin diseases related to dermal microenvironmental dysregulation.
