Poria cocos-derived exosome-like nanoparticles ameliorate lymphedema by reprogramming fibroblast metabolism via enhanced TCA cycle flux.

Lymphedema is a chronic condition characterized by impaired lymphatic drainage, leading to tissue fibrosis and functional impairment, with no effective pharmacological treatments currently available. This study investigated the therapeutic potential of Plant-Derived Exosome-like Nanoparticles (PELNs), particularly those from Poria cocos-Derived Exosome-like Nanoparticles (PcELNs), in treating lymphedema. We isolated PELNs from five botanical sources and found that PcELNs exhibited superior efficacy in alleviating lymphedema symptoms in a mouse model. Multi-omics analyses (transcriptomic, proteomic, metabolomic) revealed that PcELNs induce metabolic reprogramming in human foreskin fibroblasts (HFFs), shifting cell metabolism from glycolysis towards mitochondrial oxidative phosphorylation. This shift may be mediated through enhancing amino acid metabolism and TCA cycle flux, ultimately increasing oxidative phosphorylation. Furthermore, PcELNs reversed TGF-β-induced pro-fibrotic activation, promoting a matrix-remodeling phenotype. In vivo, PcELNs significantly ameliorated lymphedema by upregulating matrix metalloproteinases (MMP1a, MMP3) and improving mitochondrial function. Our findings demonstrate that PcELNs represent a novel and effective nanotherapeutic strategy for lymphedema by orchestrating metabolic reprogramming and inhibiting fibrosis. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-026-04200-z.