Wade T. Johnson, , , Elizabeth L. Wilkinson, , , Neha Iyer, , , Maksim Dolmat, , , Miriam Bollmann, , , Nour Dada, , , Xiaofu Wei, , , Shen Yang, , , Tiffany Zhang, , , Grace Yoo, , , Marianne Bernardo, , , Madison Price, , , Elizabeth Frame, , , Mariko Ishimori, , , Jon T. Giles, , , Wei Wang, , , Mattias N.D. Svensson, , , Nunzio Bottini*, , and , Nisarg J. Shah*,
{"title":"免疫调节纳米颗粒使联合疗法增强类风湿关节炎的疾病预防和耀斑控制","authors":"Wade T. Johnson, , , Elizabeth L. Wilkinson, , , Neha Iyer, , , Maksim Dolmat, , , Miriam Bollmann, , , Nour Dada, , , Xiaofu Wei, , , Shen Yang, , , Tiffany Zhang, , , Grace Yoo, , , Marianne Bernardo, , , Madison Price, , , Elizabeth Frame, , , Mariko Ishimori, , , Jon T. Giles, , , Wei Wang, , , Mattias N.D. Svensson, , , Nunzio Bottini*, , and , Nisarg J. Shah*, ","doi":"10.1021/acscentsci.5c00723","DOIUrl":null,"url":null,"abstract":"<p >Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. <i>In vitro</i>, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic T<sub>H</sub>17 cells. Next generation RNA sequencing of lymph node DC revealed <i>Ctla4</i> upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.</p><p >Agg-CLNP is a disease modifying agent which modulates immune activation and effectively suppresses disease onset and controls flares, providing a potential solution to unmet needs in rheumatoid arthritis.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1581–1597"},"PeriodicalIF":10.4000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00723","citationCount":"0","resultStr":"{\"title\":\"Immunomodulatory Nanoparticles Enable Combination Therapies To Enhance Disease Prevention and Flare Control in Rheumatoid Arthritis\",\"authors\":\"Wade T. Johnson, , , Elizabeth L. Wilkinson, , , Neha Iyer, , , Maksim Dolmat, , , Miriam Bollmann, , , Nour Dada, , , Xiaofu Wei, , , Shen Yang, , , Tiffany Zhang, , , Grace Yoo, , , Marianne Bernardo, , , Madison Price, , , Elizabeth Frame, , , Mariko Ishimori, , , Jon T. Giles, , , Wei Wang, , , Mattias N.D. Svensson, , , Nunzio Bottini*, , and , Nisarg J. Shah*, \",\"doi\":\"10.1021/acscentsci.5c00723\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. <i>In vitro</i>, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic T<sub>H</sub>17 cells. Next generation RNA sequencing of lymph node DC revealed <i>Ctla4</i> upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.</p><p >Agg-CLNP is a disease modifying agent which modulates immune activation and effectively suppresses disease onset and controls flares, providing a potential solution to unmet needs in rheumatoid arthritis.</p>\",\"PeriodicalId\":10,\"journal\":{\"name\":\"ACS Central Science\",\"volume\":\"11 9\",\"pages\":\"1581–1597\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00723\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Central Science\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acscentsci.5c00723\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscentsci.5c00723","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Immunomodulatory Nanoparticles Enable Combination Therapies To Enhance Disease Prevention and Flare Control in Rheumatoid Arthritis
Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.
Agg-CLNP is a disease modifying agent which modulates immune activation and effectively suppresses disease onset and controls flares, providing a potential solution to unmet needs in rheumatoid arthritis.
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.