Ginsenoside-based nanoliposomes co-delivering ergothioneine and coenzyme Q10 to combat skin aging via mitochondrial modulation.

Skin aging is closely linked to mitochondrial dysfunction, yet effective delivery of mitochondrial therapeutics to the skin remains a challenge. Here, we report ECG-Lipo, a mitochondria-modulating nanoliposome system that co-delivers hydrophilic ergothioneine (EGT) and lipophilic coenzyme Q10 (CoQ10) for rejuvenation therapy. ECG-Lipo was fabricated by flash nanoprecipitation using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and protopanaxatriol-type ginsenoside metabolites (PPTGM) as liposome-forming agents, yielding uniform nanosized unilamellar vesicles with high stability and encapsulation efficiency. Compared with free drug solutions, ECG-Lipo significantly enhanced skin penetration and cellular repair, as demonstrated by in vitro Franz diffusion assays, in vivo fluorescence imaging in mouse skin, and fibroblast migration assays. Molecular docking indicated that PPTGM exhibits stronger predicted interactions with the EGT transporter OCTN-1 than cholesterol through combined hydrophobic and hydrogen-bonding interactions, suggesting a potential structural basis for the observed biological effects. In oxidative stress-challenged human dermal fibroblasts, ECG-Lipo preserved mitochondrial integrity by maintaining mitochondrial signal and morphology, restoring membrane potential, and suppressing mitochondrial superoxide accumulation. These results highlight ECG-Lipo as a promising mitochondria-modulating nanoliposome system for transdermal delivery with potential for therapeutic intervention against intrinsic skin aging.