Epidermolysis bullosa (EB) is a rare genetic condition marked by skin fragility and persistent blistering, presenting significant challenges for efficient topical medicinal administration due to inadequate drug penetration and the instability of bioactive compounds. The objective of this study was to create and assess innovative nanocarrier technologies for enhanced topical administration of EB treatments. We produced lipid-based nanostructured lipid carriers (NLCs) and polymeric nanogels to hold curcumin and siRNA that target type VII collagen suppressor genes. The physicochemical characterization encompassed particle size, zeta potential, entrapment efficiency, and stability. The study evaluated in vitro drug release, ex vivo skin permeability with human cadaver skin, and in vivo wound healing efficiency in EB mice models. The optimized NLCs had a mean particle size of 142.6 ± 5.8 nm, a polydispersity index of 0.21 ± 0.03, a zeta potential of –28.4 ± 2.1 mV, and an entrapment efficiency of 91.3 ± 2.7%. Polymeric nanogels with a particle size of 168.2 ± 7.2 nm and an entrapment effectiveness of 87.6 ± 3.4%. There were sustained release profiles, with NLCs releasing 72.5% of the drug after 24 hours and nanogels releasing 54.2% of the drug. Ex vivo permeation experiments demonstrated a considerably greater drug deposition in epidermal layers with NLCs (5.42 ± 0.28 µg/cm²) compared to regular cream (1.87 ± 0.15 µg/cm²; p < 0.01). In vivo, EB mice with NLC-based formulations exhibited a 78.6% reduction in wound area after 14 days, in contrast to 52.1% in the nanogel-treated group and 34.7% in the control group (p < 0.001). Histological examination validated improved re-epithelialization and decreased inflammatory infiltration in NLC-treated subjects. Advanced nanocarrier systems, especially NLCs, made drugs much more stable, let them go through the skin better, and enhanced therapeutic outcomes in EB models. These results bolster the viability of nanotechnology-based topical delivery systems as a promising approach for the management of epidermolysis bullosa.