Poly(ethylene glycol)-Modified Polydopamine Nanozymes Activated by Near-Infrared Irradiation Induce White Adipocyte Browning

Abstract Obesity, as a global public health crisis, is fundamentally linked to the pathological expansion and dysfunction of white fat. White adipose tissue (WAT) browning, which activates UCP1-mediated mitochondrial thermogenesis, has emerged as a promising therapeutic target for obesity and related metabolic diseases. In this study, we developed polydopamine–polyethylene glycol (PDA–PEG) nanozymes that integrate the photothermal-tunable multienzyme activities of PDA with the stealth properties of PEG. Furthermore, the PDA–PEG nanozymes were engineered in combination with near-infrared (NIR) irradiation to induce browning of white adipocytes. Our experimental results demonstrated that PDA–PEG nanozymes showed temperature-dependent SOD- and CAT-like activities, as well as excellent photothermal properties. The combination of the PDA–PEG nanozymes and NIR markedly promoted white adipocyte browning, as indicated by morphological remodeling of lipid droplets, decreased lipid storage, increased mitochondrial levels, and upregulation of thermogenic genes, including Pparg, Sirt1, Cidea, and Ucp1. Notably, this combined treatment effectively reversed mitochondrial structural impairment and significantly increased the mitochondrial population with a well-defined and intact ultrastructure. Further mechanistic studies showed that by scavenging excess reactive oxygen species (ROS) in white adipocytes, the PDA–PEG nanozymes with NIR alleviated AMPK suppression, thus enhancing its phosphorylation and upregulating PGC-1α to coordinate mitochondrial biogenesis and UCP1 expression, ultimately driving the browning. This work presents a photothermal-enzymatic synergistic strategy to promote white adipocyte browning, thereby offering a promising therapeutic approach against obesity and related metabolic disorders.