{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:38:34Z","timestamp":1785425914204,"version":"3.56.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Science and Technology Program","award":["RCYX20200714114645131"],"award-info":[{"award-number":["RCYX20200714114645131"]}]},{"name":"Shenzhen Science and Technology Program","award":["JCYJ20230807110421045"],"award-info":[{"award-number":["JCYJ20230807110421045"]}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2024A1515030142"],"award-info":[{"award-number":["2024A1515030142"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2025A1515012796"],"award-info":[{"award-number":["2025A1515012796"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Futian District Health Research Project","award":["FTWS2022023"],"award-info":[{"award-number":["FTWS2022023"]}]},{"name":"Futian District Health Research Project","award":["FTWS2025026"],"award-info":[{"award-number":["FTWS2025026"]}]},{"name":"Research Start-up Fund of the Seventh Affiliated Hospital, Sun Yat-sen University","award":["ZSQYBRJH0011"],"award-info":[{"award-number":["ZSQYBRJH0011"]}]},{"award":["ZSQYBRJH0011"],"award-info":[{"award-number":["ZSQYBRJH0011"]}],"id":[{"id":"https:\/\/ror.org\/00rfd5b88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Conventional therapies for rheumatoid arthritis (RA) are limited by poor selectivity, insufficient modulation of the oxidative inflammatory microenvironment, and systemic side effects. Oxidative stress and macrophage-driven immune dysregulation represent critical therapeutic targets. Cinnamaldehyde (CA) and arginine (Arg) possess antioxidant, anti-inflammatory, and anti-osteoclastogenic activities, but their poor solubility, instability, and lack of targeting restrict clinical application. Here, we report a pH-responsive cinnamaldehyde\u2013arginine nanoprodrug (Arg-CA NPs), synthesized via Schiff base reaction, that spontaneously self-assembles into uniform nanoparticles capable of acid-triggered dual-drug release. Arg-CA NPs enhanced the solubility and stability of CA, exhibited excellent dispersibility and circulatory stability, and demonstrated intrinsic antioxidant and anti-inflammatory properties. Mechanistically, Arg-CA NPs attenuated intracellular ROS accumulation, preserved mitochondrial function, and reprogrammed macrophages toward an anti-inflammatory M2 phenotype by suppressing hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1), cyclooxygenase-2 (COX-2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) signaling. In an adjuvant-induced arthritis (AIA) rat model, Arg-CA NPs selectively accumulated in inflamed joints and significantly alleviated joint swelling, synovial inflammation, cartilage erosion, and bone destruction. These findings identify Arg-CA NPs as a promising redox-active nanoplatform for RA therapy by targeting oxidative stress and immune dysregulation.<\/jats:p>","DOI":"10.3390\/antiox15040469","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T09:08:12Z","timestamp":1775812092000},"page":"469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["pH-Responsive Cinnamaldehyde\u2013Arginine Nanoprodrug for Targeted Rheumatoid Arthritis Therapy via Antioxidant Activity and Macrophage Reprogramming"],"prefix":"10.3390","volume":"15","author":[{"given":"Lihong","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"},{"name":"Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dazhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, Shenzhen Nanshan Hospital, Shenzhen 518052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Kang","sequence":"additional","affiliation":[{"name":"Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2470-6756","authenticated-orcid":false,"given":"Shuo","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1016\/S0140-6736(17)31472-1","article-title":"Pathogenetic insights from the treatment of rheumatoid arthritis","volume":"389","author":"McInnes","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1097\/BOR.0b013e32832a2f02","article-title":"Long-term outcomes of rheumatoid arthritis","volume":"21","author":"Sokka","year":"2009","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Radu, A., and Bungau, S.G. (2021). Management of Rheumatoid Arthritis: An Overview. Cells, 10.","DOI":"10.3390\/cells10112857"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10018","DOI":"10.1002\/jcp.27860","article-title":"Strategies toward rheumatoid arthritis therapy; the old and the new","volume":"234","author":"Abbasi","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e001235","DOI":"10.1136\/rmdopen-2020-001235","article-title":"Risk for infections with glucocorticoids and DMARDs in patients with rheumatoid arthritis","volume":"7","author":"Riley","year":"2021","journal-title":"Rmd Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.redox.2017.01.023","article-title":"Redox regulation in metabolic programming and inflammation","volume":"12","author":"Griffiths","year":"2017","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrrheum.2011.205","article-title":"Hypoxia\u2014A key regulator of angiogenesis and inflammation in rheumatoid arthritis","volume":"8","author":"Konisti","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nrrheum.2016.69","article-title":"Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis","volume":"12","author":"Fearon","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.cbi.2017.12.024","article-title":"Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis","volume":"281","author":"Phull","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41584-022-00771-x","article-title":"Cellular metabolic adaptations in rheumatoid arthritis and their therapeutic implications","volume":"18","author":"Fearon","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nrrheum.2016.91","article-title":"Macrophage heterogeneity in the context of rheumatoid arthritis","volume":"12","author":"Udalova","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yao, Y., Cai, X., Ren, F., Ye, Y., Wang, F., Zheng, C., Qian, Y., and Zhang, M. (2021). The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.664871"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"355","DOI":"10.2174\/1389557523666230725113446","article-title":"Cinnamaldehyde as a Promising Dietary Phytochemical Against Metabolic Syndrome: A Systematic Review","volume":"24","author":"Khaafi","year":"2024","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1007\/s10787-022-01005-y","article-title":"Novel anti-arthritic mechanisms of trans-cinnamaldehyde against complete Freund\u2019s adjuvant-induced arthritis in mice: Involvement of NF-\u03baB\/TNF-\u03b1 and IL-6\/IL-23\/IL-17 pathways in the immuno-inflammatory responses","volume":"30","author":"Abdelrahman","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1007\/s10753-020-01246-5","article-title":"Cinnamaldehyde Attenuates the Progression of Rheumatoid Arthritis through Down-Regulation of PI3K\/AKT Signaling Pathway","volume":"43","author":"Li","year":"2020","journal-title":"Inflammation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106570","DOI":"10.1016\/j.intimp.2020.106570","article-title":"Cinnamaldehyde suppresses NLRP3 derived IL-1\u03b2 via activating succinate\/HIF-1 in rheumatoid arthritis rats","volume":"84","author":"Liu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_18","first-page":"70","article-title":"Cinnamaldehyde and eugenol attenuates collagen induced arthritis via reduction of free radicals and pro-inflammatory cytokines","volume":"53","author":"Mateen","year":"2019","journal-title":"Phytomed. Int. J. Phytother. Phytopharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.indcrop.2015.02.005","article-title":"Thermal stability and antioxidant activity of essential oils from aromatic plants farmed in Argentina","volume":"69","author":"Olmedo","year":"2015","journal-title":"Ind. Crops Prod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1021\/acs.jafc.9b07611","article-title":"l-Arginine Ameliorates Lipopolysaccharide-Induced Intestinal Inflammation through Inhibiting the TLR4\/NF-\u03baB and MAPK Pathways and Stimulating \u03b2-Defensin Expression in Vivo and in Vitro","volume":"68","author":"Lan","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109985","DOI":"10.1016\/j.fsi.2024.109985","article-title":"Arginine alleviates LPS-induced leukocytes inflammation and apoptosis via adjusted NODs signaling","volume":"154","author":"Qian","year":"2024","journal-title":"Fish Shellfish Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1136\/ard-2022-223626","article-title":"L-arginine metabolism inhibits arthritis and inflammatory bone loss","volume":"83","author":"Cao","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/s41467-025-56223-z","article-title":"High-density lipoprotein nanoparticles spontaneously target to damaged renal tubules and alleviate renal fibrosis by remodeling the fibrotic niches","volume":"16","author":"He","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"121938","DOI":"10.1016\/j.biomaterials.2022.121938","article-title":"Dynamic tagging to drive arginine nano-assembly to metabolically potentiate immune checkpoint blockade therapy","volume":"292","author":"Zang","year":"2023","journal-title":"Biomaterials"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0891-5849(98)00315-3","article-title":"Antioxidant activity applying an improved ABTS radical cation decolorization assay","volume":"26","author":"Re","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/S0039-9140(97)00017-9","article-title":"A highly water-soluble disulfonated tetrazolium salt as a chromogenic indicator for NADH as well as cell viability","volume":"44","author":"Ishiyama","year":"1997","journal-title":"Talanta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3203","DOI":"10.2147\/IJN.S207589","article-title":"Drug-free mannosylated liposomes inhibit tumor growth by promoting the polarization of tumor-associated macrophages","volume":"14","author":"Ye","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/0076-6879(95)60154-6","article-title":"Mitochondrial membrane potential monitored by JC-1 dye","volume":"260","author":"Reers","year":"1995","journal-title":"Methods Enzymol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-1-60761-411-1_4","article-title":"Identification of ROS using oxidized DCFDA and flow-cytometry","volume":"594","author":"Eruslanov","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1476-5381.1963.tb01508.x","article-title":"Chemotherapy of arthritis induced in rats by mycobacterial adjuvant","volume":"21","author":"Newbould","year":"1963","journal-title":"Br. J. Pharmacol. Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6458","DOI":"10.1021\/acsnano.8b02881","article-title":"Quantitative Assessment of Nanoparticle Biodistribution by Fluorescence Imaging, Revisited","volume":"12","author":"Meng","year":"2018","journal-title":"Acs Nano"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1186\/s11671-018-2728-6","article-title":"Insight into Cellular Uptake and Intracellular Trafficking of Nanoparticles","volume":"13","author":"Foroozandeh","year":"2018","journal-title":"Nanoscale Res. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100223","DOI":"10.1016\/j.mtbio.2022.100223","article-title":"Advanced application of stimuli-responsive drug delivery system for inflammatory arthritis treatment","volume":"14","author":"Zhang","year":"2022","journal-title":"Mater. Today Bio"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jconrel.2022.05.056","article-title":"Preparation and application of pH-responsive drug delivery systems","volume":"348","author":"Ding","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41565-021-00858-8","article-title":"Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics","volume":"16","author":"Rennick","year":"2021","journal-title":"Nat. Nanotechnol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8655","DOI":"10.1021\/acsnano.5b03184","article-title":"Physical Principles of Nanoparticle Cellular Endocytosis","volume":"9","author":"Zhang","year":"2015","journal-title":"Acs Nano"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release","volume":"94","author":"Zorov","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_38","first-page":"1481","article-title":"The synthesis of novel Schiff base antioxidants to promote anti-thermal aging properties of natural rubber","volume":"71","author":"Zhang","year":"2017","journal-title":"Chem. Zvesti"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/cr.2015.68","article-title":"Metabolic reprogramming in macrophages and dendritic cells in innate immunity","volume":"25","author":"Kelly","year":"2015","journal-title":"Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103123","DOI":"10.1016\/j.redox.2024.103123","article-title":"Redox regulation of macrophages","volume":"72","author":"Tran","year":"2024","journal-title":"Redox Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0049-0172(03)00134-3","article-title":"Cyclooxygenase-2 and prostaglandins in articular tissues","volume":"33","author":"Pelletier","year":"2003","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the pathogenesis of rheumatoid arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","first-page":"23","article-title":"Recent advances in nano-targeting drug delivery systems for rheumatoid arthritis treatment","volume":"2","author":"Li","year":"2023","journal-title":"Acta Mater. Medica"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.addr.2012.03.006","article-title":"Development of macromolecular prodrug for rheumatoid arthritis","volume":"64","author":"Yuan","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41584-022-00793-5","article-title":"Mechanisms of joint destruction in rheumatoid arthritis\u2014Immune cell-fibroblast-bone interactions","volume":"18","author":"Komatsu","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Maeda, K., Yoshida, K., Nishizawa, T., Otani, K., Yamashita, Y., Okabe, H., Hadano, Y., Kayama, T., Kurosaka, D., and Saito, M. (2022). Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052871"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/469\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T04:19:05Z","timestamp":1775967545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/469"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["antiox15040469"],"URL":"https:\/\/doi.org\/10.3390\/antiox15040469","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]}}}