Reducing individual inflammatory factors does not always translate into clinical efficacy in rheumatoid arthritis (RA), an autoimmune disease characterized by joint inflammation. Proinflammatory M1 macrophages are a key driver of the hyperinflammatory joint microenvironment, which also promotes the progression of RA. Here we show that folate-receptor-targeted photosynthetic nanothylakoid (FA-PEG-NTK)-based phototherapy reprogrammes macrophages from M1 to anti-inflammatory M2, and successfully remodels the inflammatory RA microenvironment. The nanothylakoids were sourced from plant-derived thylakoids and developed by surface modification with distearoyl phosphoethanolamine-polyethylene glycol (PEG) via hydrophobic interactions to preserve their photocatalytic enzymes. We show that upon light irradiation in a mouse macrophage model of inflammation, the FA-PEG-NTK system generates oxygen and nicotinamide adenine dinucleotide phosphate, alleviating hypoxia and reducing reactive oxygen species. This rebalances the oxidative stress in M1 macrophages, thereby remodelling the inflammatory microenvironment in RA. We also show that in a collagen-induced arthritis rat model, FA-PEG-NTK-mediated phototherapy notably alleviated synovial hyperplasia and enhanced bone and cartilage regeneration, outperforming the clinical treatment methotrexate, with no apparent side effects.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.