Nature Nanotechnology
http://www.nature.com/nnano/current_issue/rss/
Ziyue Li
Abstract
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.
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Data availability
All the data supporting the findings of this study are presented in the Article and its Supplementary Information. The bulk transcriptome and single-cell RNA sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive (SRA) under the BioProject accession number PRJNA1312955 and PRJNA1314299. The proteomics data have been deposited in the iProX database under accession number IPX0013257000. Source data are provided with this paper.
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Acknowledgements
The work was supported by grants from the National Key Research and Development Program of China (no. 2023YFF0714200 to Z.S.), the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB0930000 to H.Z.), the National Natural Science Foundation of China (nos. 92159304, 82372022 and 82227806 to Z.S.; nos. 82171958 and 82572255 to D.H.; no. 82271998 to Y.L.), the Shenzhen Medical Research Fund (no. B2302021 to Z.S.), the Guangdong Basic and Applied Basic Research Fund (no. 2024A1515030212 to D.G.), the Guangzhou Municipal Science and Technology Department: 2023 Key research and development plan projects (no. 2023B03J1350 to Y.L.), the Shenzhen Outstanding Talents Training Fund (to H.Z.), and the China-Singapore International Joint Laboratory for Rare Earth Imaging Materials and Devices (to Z.S.). W.T. acknowledges the support from the Harvard /Brigham Health & Technology Innovation Fund (no. 2023A004452 to W.T.), Nanotechnology Foundation (no. 2022A002721 to W.T.), and Distinguished Chair Professorship Foundation (no. 018129 to W.T.). We thank C. Liu, Y. Ren and S. Qiao for technical support with photoacoustic blood oxygenation imaging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Shanghai Luming Biological Technology for providing proteomics services.
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Z. Li, Y.Y. and Y.S. conceived and designed the study. Z. Li and Y.Y. performed research. Z. Li and Y.Y. conducted the experiments. Z. Li, Y.Y., Y.S., D.H., D.G., Y.Z. and H.Y. performed data analysis. H.Q. and Y. Liu provided clinical samples. Z. Li, Z. Luo, Q.S., N.K., Y. Li, H.Z., W.T. and Z.S. wrote and revised the paper. All authors discussed the results and approved the final paper.
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W.T. consults for (or serves on scientific advisory boards), has lectured (and received a fee), or conducts sponsored research at Harvard Medical School/Brigham and Women’s Hospital for the following entities: Novo Nordisk A/S, Henlius USA Inc. The other authors declare no competing interests.
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Li, Z., Yang, Y., Shi, Y. et al. Bioengineered photosynthetic nanothylakoids reshape the inflammatory microenvironment for rheumatoid arthritis therapy.
Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-02063-3
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DOI: https://doi.org/10.1038/s41565-025-02063-3
