{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T22:33:16Z","timestamp":1785882796826,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Natural Science Foundation","award":["82003258"],"award-info":[{"award-number":["82003258"]}]},{"name":"Science Foundation of Chengdu","award":["2019-YF05-00639-SN"],"award-info":[{"award-number":["2019-YF05-00639-SN"]}]},{"name":"the Scientific Research Program of Health Commission of Sichuan Province","award":["20PJ097"],"award-info":[{"award-number":["20PJ097"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)\u2013cholesterol\u2013polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) p65 siRNA, the p65 siRNA\/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA\/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.<\/jats:p>","DOI":"10.3390\/pharmaceutics14010162","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T20:33:04Z","timestamp":1641933184000},"page":"162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8966-2582","authenticated-orcid":false,"given":"Xiaohua","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China"},{"name":"Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailing","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieping","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Shuai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-9961","authenticated-orcid":false,"given":"Ke","family":"Men","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmei","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.jconrel.2020.07.006","article-title":"Nanoparticle-siRNA: A potential strategy for rheumatoid arthritis therapy?","volume":"325","author":"Feng","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.4155\/tde-2020-0029","article-title":"Targeted drug-delivery systems in the treatment of rheumatoid arthritis: Recent advancement and clinical status","volume":"11","author":"Gorantla","year":"2020","journal-title":"Ther. Deliv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/jimd.12093","article-title":"Exploiting epigenetics for the treatment of inborn errors of metabolism","volume":"43","author":"Rutten","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/35078107","article-title":"Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells","volume":"411","author":"Elbashir","year":"2001","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rai, M.F., Pan, H., Yan, H., Sandell, L.J., Pham, C.T.N., and Wickline, S.A. (2019). Applications of RNA interference in the treatment of arthritis. Transl. Res., 214.","DOI":"10.1016\/j.trsl.2019.07.002"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.addr.2020.07.022","article-title":"Recent advances in siRNA delivery mediated by lipid-based nanoparticles","volume":"154","author":"Yonezawa","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.addr.2019.05.004","article-title":"Strategies, design, and chemistry in siRNA delivery systems","volume":"144","author":"Dong","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijpharm.2021.120851","article-title":"Innovative lipoplexes formulations with enhanced siRNA efficacy for cancer treatment: Where are we now?","volume":"605","author":"Berger","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Roszkowski, L., and Ciechomska, M. (2021). Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis. Cells, 10.","DOI":"10.3390\/cells10081860"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Makuch, S., Wiecek, K., and Wozniak, M. (2021). The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis. Pharmaceuticals, 14.","DOI":"10.3390\/ph14040309"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.bcp.2019.03.029","article-title":"The many facets of macrophages in rheumatoid arthritis","volume":"165","author":"Siouti","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.clim.2021.108793","article-title":"Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis","volume":"230","author":"Liu","year":"2021","journal-title":"Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.biomaterials.2020.120390","article-title":"Targeted silver nanoparticles for rheumatoid arthritis therapy via macrophage apoptosis and Re-polarization","volume":"264","author":"Yang","year":"2021","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, T., Zhang, L., Joo, D., and Sun, S.C. (2017). NF-kappaB signaling in inflammation. Signal. Transduct Target. Ther, 2.","DOI":"10.1038\/sigtrans.2017.23"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.autrev.2020.102741","article-title":"An Overview of the NF-kB mechanism of pathophysiology in rheumatoid arthritis, investigation of the NF-kB ligand RANKL and related nutritional interventions","volume":"20","author":"Ilchovska","year":"2021","journal-title":"Autoimmun. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.intimp.2021.107657","article-title":"Decursin alleviates the aggravation of osteoarthritis via inhibiting PI3K-Akt and NF-kB signal pathway","volume":"97","author":"He","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ijpharm.2020.120033","article-title":"Assembly strategy of liposome and polymer systems for siRNA delivery","volume":"592","author":"Song","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Miron-Barroso, S., Domenech, E.B., and Trigueros, S. (2021). Nanotechnology-Based Strategies to Overcome Current Barriers in Gene Delivery. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168537"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1488497","DOI":"10.1080\/20022727.2018.1488497","article-title":"Polyethylenimine-based nanocarriers in co-delivery of drug and gene: A developing horizon","volume":"9","author":"Zakeri","year":"2018","journal-title":"Nano Rev. Exp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/admt.202001236","article-title":"Nanoparticle-Mediated siRNA Delivery and Multifunctional Modification Strategies for Effective Cancer Therapy","volume":"6","author":"Chen","year":"2021","journal-title":"Adv. Mater. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1088\/1361-6528\/aa5e56","article-title":"Enhanced gene transfection performance and biocompatibility of polyethylenimine through pseudopolyrotaxane formation with alpha-cyclodextrin","volume":"28","author":"Hu","year":"2017","journal-title":"Nanotechnology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1007\/s11095-017-2175-6","article-title":"Anti-Inflammatory Therapeutic Effect of Adiponectin Gene Delivery Using a Polymeric Carrier in an Acute Lung Injury Model","volume":"34","author":"Piao","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.2174\/0929867325666181031094759","article-title":"Polyethylenimine-based Formulations for Delivery of Oligonucleotides","volume":"26","author":"Hao","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1007\/s13233-019-7027-2","article-title":"Bioreducible Polyspermine-Based Gene Carriers for Efficient siRNA Delivery: Effects of PEG Conjugation on Gene Silencing Efficiency","volume":"26","author":"Bhang","year":"2018","journal-title":"Macromol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13317-020-00135-z","article-title":"NF-\u03baB signaling in rheumatoid arthritis with focus on fibroblast-like synoviocytes","volume":"11","author":"Farhadi","year":"2020","journal-title":"Autoimmun. Highlights"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41573-019-0017-4","article-title":"The current state and future directions of RNAi-based therapeutics","volume":"18","author":"Setten","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, H., Zhang, S., Lv, J., and Cheng, Y. (2021). Design of polymers for siRNA delivery: Recent progress and challenges. View, 2.","DOI":"10.1002\/VIW.20200026"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s13346-016-0306-y","article-title":"Optimized polyethylenimine (PEI)-based nanoparticles for siRNA delivery, analyzed in vitro and in an ex vivo tumor tissue slice culture model","volume":"7","author":"Ewe","year":"2017","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.actbio.2017.11.036","article-title":"Combinational siRNA delivery using hyaluronic acid modified amphiphilic polyplexes against cell cycle and phosphatase proteins to inhibit growth and migration of triple-negative breast cancer cells","volume":"66","author":"Parmar","year":"2018","journal-title":"Acta Biomaterialia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4698","DOI":"10.1039\/C9BM01025D","article-title":"Nanoparticle-delivered siRNA targeting Bruton\u2019s tyrosine kinase for rheumatoid arthritis therapy","volume":"7","author":"Zhao","year":"2019","journal-title":"Biomater. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.2147\/IJN.S155537","article-title":"Superparamagnetic iron oxide nanoparticles modified with polyethylenimine and galactose for siRNA targeted delivery in hepatocellular carcinoma therapy","volume":"13","author":"Yang","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1166\/jbn.2020.2961","article-title":"Current Progress in Messenger RNA-Based Gene Therapy","volume":"16","author":"Lei","year":"2020","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jbspin.2020.105091","article-title":"New insights into macrophage heterogeneity in rheumatoid arthritis","volume":"88","author":"Hannemann","year":"2021","journal-title":"Joint Bone Spine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s10787-021-00815-w","article-title":"Infliximab prevents systemic bone loss and suppresses tendon inflammation in a collagen-induced arthritis rat model","volume":"29","author":"Poutoglidou","year":"2021","journal-title":"Inflammopharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jconrel.2020.07.005","article-title":"Targeting interleukin-4 to the arthritic joint","volume":"326","author":"Spieler","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s11010-011-1006-z","article-title":"Effect of RNAi-induced down regulation of nuclear factor kappa-B p65 on acute monocytic leukemia THP-1 cells in vitro and vivo","volume":"359","author":"Wang","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4471","DOI":"10.1021\/acsami.7b17109","article-title":"Branched Glycerol-Based Copolymer with Ultrahigh p65 siRNA Delivery Efficiency for Enhanced Cancer Therapy","volume":"10","author":"Zhou","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4363","DOI":"10.1172\/JCI75673","article-title":"Peptide-siRNA nanocomplexes targeting NF-\u03baB subunit p65 suppress nascent experimental arthritis","volume":"124","author":"Zhou","year":"2014","journal-title":"J. Clin. Investig."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:01:59Z","timestamp":1760364119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,11]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["pharmaceutics14010162"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14010162","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,11]]}}}