Polyphenol-rapamycin self-assembled nanoparticles for inflammatory diseases treatment by regulating macrophage mitochondrial homeostasis and polarization reprogramming

Inflammatory diseases pose a severe global health burden, accounting for over 50% of global deaths. Mounting evidence indicates that macrophage homeostasis imbalance is a key pathogenic driver, involving a critical pathological cascade. Notably, excessive reactive oxygen species (ROS) accumulation in macrophages induces mitochondrial damage, which in turn triggers the dysregulation of M1/M2 polarization, ultimately exacerbating inflammatory progression. However, existing approaches for the concurrent resolution of these issues are rather scarce. Herein, the mitochondrion-targeted epigallocatechin gallate (EGCG)-rapamycin (RAPA) self-assembled nanoparticles (ER NPs) are designed for overcoming the limitations of single-function therapeutic platforms. In vitro studies demonstrate that ER NPs efficiently scavenge intracellular and mitochondrial ROS, restoring cellular redox balance. Concurrently, they restore the mitochondrial membrane potential (MMP) and increase ATP biosynthesis, thereby reestablishing mitochondrial homeostasis. Furthermore, ER NPs reshape a stable anti-inflammatory immune microenvironment by modulating macrophage polarization toward the protective M2 type. In vivo validation in mouse models of periodontitis, diabetic skin wounds, and sepsis reveals that compared with free RAPA, ER NPs exhibit significantly superior anti-inflammatory activity, effectively alleviating tissue damage induced by excessive inflammation. Collectively, this mitochondria-targeted, multifunctional self-assembled nanosystem directly targets the core pathological cascade of macrophage homeostasis imbalance, providing a promising therapeutic strategy for inflammatory diseases.