Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)-targeted Gel/Mg/Lip@Gigantol nanoplatform attenuates skin barrier disruption-associated aging in mice via NLRP3 suppression.

Skin aging serves as a critical indicator of systemic health decline. Despite Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) being a key therapeutic target, mechanistic understanding remains incomplete and potent, safe activators are lacking, hindering clinical progress. This study proposes the "Barrier-Skin-Systemic Aging Axis," demonstrating that epidermal barrier disruption accelerates aging via PPARγ suppression. This suppression triggers NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation, amplifies the Senescence-Associated Secretory Phenotype (SASP), and induces systemic oxidative stress, establishing PPARγ as the central mechanistic hub. To address PPARγ activation challenges, Gigantol-a natural bibenzyl identified from Dendrobium through structure-activity screening-was characterized as a high-affinity PPARγ agonist (Kd = 1.76 × 10-6 M) exhibiting superior potency and safety compared to pioglitazone. A hierarchical Gel/Mg/Lip delivery system was engineered, integrating liposomal transdermal enhancement, thermosensitive hydrogel sustain-release, and magnesium-mediated barrier repair to potentiate PPARγ targeting (2.32-fold increase in targeting efficiency). In vivo, Gel/Mg/Lip@Gigantol effectively delayed skin aging progression, restored barrier microstructure, and suppressed systemic inflammation, with key aging indicators outperforming existing strategies (3.12-fold reduction in P21). This research achieves dual breakthroughs: mechanistically, by elucidating the PPARγ-driven aging axis to establish a new therapeutic paradigm; and technologically, through the development of a macromolecular-scale targeting strategy (leveraging Gigantol-PPARγ interaction + Gel/Mg/Lip dual targeting) enabling simultaneous inflammaging blockade and barrier restoration. This integrated approach opens transformative pathways for longevity research and precision anti-aging interventions.