Selenium‑based nanotherapeutics promote healing of infected diabetic wounds via photothermal‑driven macrophage immunometabolic reprogramming and the NRF2/HIF‑1α axis

Infected wounds heal considerably slowly among patients with diabetes because of biofilm barriers and immune dysregulation. Therefore, treatment strategies must simultaneously eliminate infection and accelerate healing. In this study, we present a dual-mechanism nanoplatform composed of indocyanine green (ICG)-loaded lentinan (LNT)‑functionalized selenium nanoparticles (ICG@LNT‑SeNPs). This platform disrupts the pathological cycle by integrating near‑infrared‑triggered photothermal eradication of methicillin-resistant Staphylococcus aureus (MRSA) biofilms with selenium‑driven immunometabolic reprogramming of macrophages. The selenium (Se) component facilitates metabolic adaptation and functional remodeling of pro‑inflammatory macrophages by activating the NRF2/HIF‑1α axis, inducing transition into an M2 phenotype, which is characterized by elevated expression of repair‑associated factors (e.g., Il10 and Arg1). ICG@LNT‑SeNPs also enhance the defensive properties of cellular antioxidants by upregulating the expression of Secisbp2 (a key regulator of selenoprotein biosynthesis), Gpx4, and Txnrd2. This combined antibacterial‑metabolic‑immune mechanism causes vascular endothelial cells and fibroblasts to migrate, enhancing subsequent collagen deposition and angiogenesis and, thus, accelerating wound closure. This mechanism demonstrated more mature tissue reconstruction in diabetic mice with MRSA-infected wounds. Overall, the proposed SeNPs-based therapeutic strategy promotes infected diabetic wounds healing through macrophage immunometabolic reprogramming. The findings may help identify new targets and provide insights for developing promising management approaches for chronic wounds.