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

  • Int J Biol Macromol. 2025 Sep 5;328(Pt 1):147464. doi: 10.1016/j.ijbiomac.2025.147464.
Xiaorong Jia  1 ,  Ruihong Yuan  2 ,  Yihang Huang  3 ,  Xiwei Li  1 ,  Runnan Zhang  1 ,  Li He  1 ,  Zhi Yang  4
Affiliations
  • 1. Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 2. Department of Plastic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 3. The third Affiliated Hospital of Kunming Medical University, Peking University Caner Hospital Yunnan, Yunnan Cancer Hospital, Kunming, 6501002, China.
  • 4. Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China. Electronic address: [email protected].
PMID: 40915461 DOI: 10.1016/j.ijbiomac.2025.147464
Abstract

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.

Keywords
Gigantol; Liposomal hydrogel; PPARγ.
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