Au₂₅ Clusterzymes-Loaded Dissolvable Microneedles Induce Browning of White Adipose Tissue and Fight Obesity

Obesity, characterized by excessive lipid storage, has become a global epidemic that severely impacts health and quality of life. Current anti-obesity strategies have encountered a range of challenges and limitations in practice. Metal clusters have recently emerged as a novel class of nanomaterials, with excellent enzyme-mimicking properties and highly effective in scavenging reactive oxygen species (ROS). In this study, atomically precise Au₂₅ clusterzymes encapsulated dissolvable microneedles (Au₂₅@DMNs) as the transdermal drug delivery system are developed to treat high-fat diet (HFD)-induced obesity. After six weeks of treatment (once every two days), the Au₂₅@DMNs group showed a significant reduction in weight gain, with a 21% decrease compared to the HFD group. Au₂₅@DMNs treatment also effectively reduced fat accumulation, improved glucose homeostasis, and alleviated lipid metabolism disorders. Especially, Au₂₅@DMNs treatment significantly mitigated chronic inflammation in white adipose tissue (WAT) and even alleviated systemic inflammation. Further studies revealed that Au₂₅ clusterzymes from Au₂₅@DMNs neutralized microenvironmental ROS, which in turn triggered WAT browning via the AMPK/PGC-1α pathway, thus achieving high efficiency in anti-obesity. These findings demonstrate that transdermal delivery of clusterzymes via dissolvable microneedles can effectively induce WAT browning and thermogenesis, thus providing a new platform for combating obesity and related metabolic disorders.