{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:06:55Z","timestamp":1788876415912,"version":"build-2803163510"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"35","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease fueled by abnormal immune responses and metabolic dysregulation, often leading to life-threatening lupus nephritis (LN). While Cyclosporine A (CsA) is a potent therapeutic agent, its clinical utility is severely constrained by systemic off-target toxicity and the necessity for frequent, high-dose administration. This study evaluates P2Ns-GA-CsA, a receptor-mediated, targeted nanoparticle formulation designed to modulate the core immune-metabolic axis in LN. Using an NZBWF1\/J murine model, the administration of P2Ns-GA-CsA achieves enhanced renal protection compared to conventional oral CsA (Neoral), effectively suppressing serum creatinine, clusterin, and proinflammatory cytokines while preserving renal histoarchitecture. This therapeutic efficacy is realized with less than half the dosing frequency of the clinical standard, requiring 42 doses versus 98 doses over a 14 week period. Mechanistically, P2Ns-GA-CsA treatment is associated with the restoration of gut microbial homeostasis through the enrichment of protective taxa (Lactobacillus and Muribaculaceae), facilitating a metabolic shift. This modulation of the gut-microbial metabolic axis promotes the anti-inflammatory indole pathway while suppressing the pathogenic indoleamine 2,3-dioxygenase 1 (IDO1)-kynurenine pathway. These findings demonstrate that this targeted nanotherapeutic strategy decouples the immunosuppressive benefits of CsA from its systemic toxicity while restoring gut-renal integrity in autoimmune disorders.<\/jats:p>","DOI":"10.1021\/acsnano.6c03606","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:02:14Z","timestamp":1786366934000},"page":"24334-24352","source":"Crossref","is-referenced-by-count":0,"title":["Cyclosporine-A\nNanotherapeutics Ameliorate\nLupus Nephritis by Reprogramming the Gut-Microbial Metabolic Axis\nand Systemic Inflammation"],"prefix":"10.1021","volume":"20","author":[{"given":"Kabirat T.","family":"Babalola","sequence":"first","affiliation":[{"name":"The University of Alabama , , AIME Building , Box 870204, , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-5170","authenticated-orcid":true,"given":"Raghu","family":"Ganugula","sequence":"additional","affiliation":[{"name":"The University of Alabama , , AIME Building , Box 870204, , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , SEC 1325 , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3809-3153","authenticated-orcid":true,"given":"Meenakshi","family":"Arora","sequence":"additional","affiliation":[{"name":"The University of Alabama , , AIME Building , Box 870204, , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , SEC 1325 , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35294"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep K.","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine , , One Baylor Plaza , , ,","place":["Houston, Texas, United States, 77030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra","family":"Mohan","sequence":"additional","affiliation":[{"name":"University of Houston , , , ,","place":["Houston, Texas, United States, 77204"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babak J.","family":"Mehrara","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center , , , ,","place":["West Harrison, New York, United States, 10604"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5606-401X","authenticated-orcid":true,"given":"M. N. V. Ravi","family":"Kumar","sequence":"additional","affiliation":[{"name":"The University of Alabama , , AIME Building , Box 870204, , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"The University of Alabama , , SEC 1325 , , ,","place":["Tuscaloosa, Alabama, United States, 35401"]},{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35294"]},{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35294"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"2026090809095351700_cit1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.coi.2020.10.014","article-title":"Type I interferon in the pathogenesis of systemic lupus\nerythematosus","volume":"67","author":"Postal","year":"2020","journal-title":"Curr. Opin. Immunol."},{"issue":"1","key":"2026090809095351700_cit2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s12519-019-00229-3","article-title":"Immunological\npathogenesis and treatment of systemic lupus erythematosus","volume":"16","author":"Pan","year":"2020","journal-title":"World J. Pediatr."},{"issue":"2","key":"2026090809095351700_cit3","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1124\/pharmrev.123.000938","article-title":"Leveraging Lymphatic System Targeting\nin Systemic Lupus\nErythematosus for Improved Clinical Outcomes","volume":"76","author":"Babalola","year":"2024","journal-title":"Pharmacol. Rev."},{"issue":"9","key":"2026090809095351700_cit4","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1161\/ATVBAHA.120.314037","article-title":"Metabolic Reprogramming\nin Immune Response and Tissue Inflammation","volume":"40","author":"Sun","year":"2020","journal-title":"Arterioscler., Thromb., Vasc. Biol."},{"issue":"1","key":"2026090809095351700_cit5","doi-asserted-by":"publisher","first-page":"iqad005","DOI":"10.1093\/oxfimm\/iqad005","article-title":"A cellular overview of immunometabolism\nin systemic\nlupus erythematosus","volume":"4","author":"Psarras","year":"2023","journal-title":"Oxf Open Immunol"},{"issue":"6","key":"2026090809095351700_cit6","doi-asserted-by":"publisher","first-page":"5742","DOI":"10.3390\/ijms24065742","article-title":"The Tryptophan and Kynurenine Pathway\nInvolved in the Development of Immune-Related Diseases","volume":"24","author":"Tsuji","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"2026090809095351700_cit7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4137\/ijtr.s2097","article-title":"Kynurenine\npathway metabolites in humans: disease and\nhealthy States","volume":"2","author":"Chen","year":"2009","journal-title":"Int. J. Tryptophan Res."},{"issue":"8","key":"2026090809095351700_cit8","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1038\/s41564-024-01737-3","article-title":"Dietary fibre directs microbial tryptophan metabolism\nvia metabolic interactions in the gut microbiota","volume":"9","author":"Sinha","year":"2024","journal-title":"Nat. Microbiol."},{"issue":"24","key":"2026090809095351700_cit9","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb3900","article-title":"A highly potent lymphatic system-targeting\nnanoparticle cyclosporine\nprevents glomerulonephritis in mouse model of lupus","volume":"6","author":"Ganugula","year":"2020","journal-title":"Sci. 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Today"},{"issue":"21","key":"2026090809095351700_cit12","doi-asserted-by":"publisher","first-page":"7203","DOI":"10.1021\/jacs.6b13231","article-title":"Next\nGeneration Precision-Polyesters Enabling Optimization of Ligand-Receptor\nStoichiometry for Modular Drug Delivery","volume":"139","author":"Ganugula","year":"2017","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026090809095351700_cit13","doi-asserted-by":"publisher","first-page":"1182193","DOI":"10.3389\/fcvm.2023.1182193","article-title":"Cardiovascular changes in the NZB\/W F1 mouse model of lupus nephritis","volume":"10","author":"Bo\u0308hme","year":"2023","journal-title":"Front. Cardiovasc. Med."},{"key":"2026090809095351700_cit14","doi-asserted-by":"publisher","first-page":"271694","DOI":"10.1155\/2011\/271694","article-title":"Murine models\nof systemic lupus erythematosus","volume":"2011","author":"Perry","year":"2011","journal-title":"J. Biomed.\nBiotechnol."},{"issue":"5","key":"2026090809095351700_cit15","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.5114\/aoms.2020.96617","article-title":"Renal involvement in systemic lupus\nerythematosus: additional histopathological lesions","volume":"19","author":"Pereira Re\u0302go Muniz","year":"2023","journal-title":"Arch. Med. Sci."},{"issue":"5","key":"2026090809095351700_cit16","doi-asserted-by":"publisher","first-page":"825","DOI":"10.2215\/CJN.05780616","article-title":"Update on Lupus Nephritis","volume":"12","author":"Almaani","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"issue":"6","key":"2026090809095351700_cit17","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.autrev.2005.01.006","article-title":"Animal models of spontaneous and drug-induced cutaneous\nlupus erythematosus","volume":"4","author":"Furukawa","year":"2005","journal-title":"Autoimmun. 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Pharmacol.\nToxicol."},{"issue":"3","key":"2026090809095351700_cit19","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1111\/apha.12764","article-title":"Biomarkers\nin acute kidney injury - pathophysiological basis and clinical performance","volume":"219","author":"Schrezenmeier","year":"2017","journal-title":"Acta Physiol"},{"issue":"5","key":"2026090809095351700_cit20","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.3390\/biomedicines11051356","article-title":"Osteopontin as a Biomarker in Chronic Kidney Disease","volume":"11","author":"Sinha","year":"2023","journal-title":"Biomedicines"},{"issue":"7","key":"2026090809095351700_cit21","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1016\/j.ekir.2025.04.035","article-title":"Urinary\nClusterin is a Biomarker of Renal Epithelial\nSenescence and Predicts Human Kidney Disease Progression","volume":"10","author":"Baird","year":"2025","journal-title":"Kidney Int. 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Immunol."},{"issue":"6","key":"2026090809095351700_cit24","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.67","article-title":"Interferon-\u03b3\nderived from cytotoxic lymphocytes directly enhances their motility\nand cytotoxicity","volume":"8","author":"Bhat","year":"2017","journal-title":"Cell Death Dis."},{"issue":"2\u20133","key":"2026090809095351700_cit25","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/S0162-3109(00)00192-2","article-title":"Mechanisms of action of cyclosporine","volume":"47","author":"Matsuda","year":"2000","journal-title":"Immunopharmacology"},{"key":"2026090809095351700_cit26","doi-asserted-by":"publisher","first-page":"115976","DOI":"10.1016\/j.biopha.2023.115976","article-title":"Polysaccharides\nregulate Th1\/Th2 balance: A new strategy for tumor immunotherapy","volume":"170","author":"Shang","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"2026090809095351700_cit27","doi-asserted-by":"publisher","first-page":"432595","DOI":"10.1155\/2011\/432595","article-title":"Inflammatory cytokines\nin systemic lupus erythematosus","volume":"2011","author":"Ohl","year":"2011","journal-title":"Biomed Res.\nInt."},{"issue":"4","key":"2026090809095351700_cit28","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1002\/jlb.64.4.494","article-title":"The murine neutrophil-chemoattractant\nchemokines LIX, KC, and MIP-2 have distinct induction kinetics, tissue\ndistributions, and tissue-specific sensitivities to glucocorticoid\nregulation in endotoxemia","volume":"64","author":"Rovai","year":"1998","journal-title":"J. Leukoc Biol."},{"issue":"9","key":"2026090809095351700_cit29","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1369\/0022155419852932","article-title":"Renal Inflammation\nand Fibrosis:\nA Double-edged Sword","volume":"67","author":"Black","year":"2019","journal-title":"J. Histochem. Cytochem."},{"issue":"4","key":"2026090809095351700_cit30","doi-asserted-by":"publisher","DOI":"10.1128\/aem.02288-17","article-title":"Gut Microbiota\nin\nHuman Systemic Lupus Erythematosus and a Mouse Model of Lupus","volume":"84","author":"Luo","year":"2018","journal-title":"Appl. Environ. Microbiol."},{"issue":"1","key":"2026090809095351700_cit31","doi-asserted-by":"publisher","first-page":"22953","DOI":"10.1038\/s41598-021-02422-9","article-title":"Fecal microbiota changes in NZB\/W F1 mice after induction\nof lupus disease","volume":"11","author":"Chen","year":"2021","journal-title":"Sci. Rep."},{"issue":"1","key":"2026090809095351700_cit32","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/s41467-020-20746-4","article-title":"Clostridioides difficile\nexploits toxin-mediated inflammation to alter the host nutritional\nlandscape and exclude competitors from the gut microbiota","volume":"12","author":"Fletcher","year":"2021","journal-title":"Nat. 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Environ.\nMicrobiol."},{"issue":"1","key":"2026090809095351700_cit36","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2022-000776","article-title":"Gut microbiota in SLE: from animal\nmodels to clinical evidence and pharmacological perspectives","volume":"10","author":"Toumi","year":"2023","journal-title":"Lupus Sci. Med."},{"key":"2026090809095351700_cit37","doi-asserted-by":"publisher","first-page":"759095","DOI":"10.3389\/fphar.2021.759095","article-title":"The Microbiota in Systemic Lupus Erythematosus: An Update on the\nPotential Function of Probiotics","volume":"12","author":"Guo","year":"2021","journal-title":"Front. Pharmacol."},{"key":"2026090809095351700_cit38","doi-asserted-by":"publisher","first-page":"923754","DOI":"10.3389\/fimmu.2022.923754","article-title":"Lactobacillus spp. act\nin synergy to attenuate splenomegaly and lymphadenopathy\nin lupus-prone MRL\/lpr mice","volume":"13","author":"Cabana-Puig","year":"2022","journal-title":"Front. 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Med."},{"issue":"1","key":"2026090809095351700_cit45","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/s41420-025-02624-4","article-title":"Inhibition\nof VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis\nin the murine lupus nephritis model","volume":"11","author":"Wang","year":"2025","journal-title":"Cell Death\nDiscov."},{"issue":"7","key":"2026090809095351700_cit46","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nmeth.3869","article-title":"DADA2: High-resolution\nsample inference from Illumina\namplicon data","volume":"13","author":"Callahan","year":"2016","journal-title":"Nat. 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