Abstract: Received: 7 March 2021 Revised: 2 September 2021 Accepted: 4 September 2021 DOI: 10.1002/ptr.7294 RESEARCH ARTICLE A triple-blind, placebo-controlled, randomized clinical trial to evaluate the effect of curcumin-containing nanomicelles on cellular immune responses subtypes and clinical outcome in COVID-19 patients Mehdi Hassaniazad1 | Ebrahim Eftekhar2 | Behnaz Rahnama Inchehsablagh3,4 | Hossein Kamali3 | Abdolali Tousi3 | Mahmoud Reza Jaafari5,6,7 | Milad Rafat3 | Mohammad Fathalipour8 | Sara Nikoofal-Sahlabadi9 | Hesam Alizade1 | Amin Reza Nikpoor10 Hamed Gouklani1 | 1 Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 2 Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 3 Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 4 Department of Physiology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 5 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 6 Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran 7 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 8 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 9 Department of Pharmaceutics, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 10 Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran Correspondence Amin Reza Nikpoor, Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Email: nikpoora@hums.ac.ir; nikpoora@ gmail.com In COVID-19 patients, cytokine storm due to excessive immune responses can cause severe complications. In this study, we investigated the effect of curcumin nanomicelles on clinical outcome and cellular immune responses subtypes changes in COVID-19 patients. A randomized, triple-blinded, placebo-controlled study was done. Forty COVID-19 patients were included into two groups of nano-curcumin and pla- Funding information The financial supports of Hormozgan University of Medical Sciences, Bandar Abbas, Iran (grant no. 990126) is acknowledged. The Exir Nano Sina company had no role in funding or dedication of SinaCurcumin and placebo capsules, data collection, analysis, and interpretation of data. cebo. The nano-curcumin group received 40 mg of nano-curcumin capsule, four times per day for 2 weeks. Clinical signs and gene expression of TBX21, GATA3, RORC and FOXP3 genes and IFN-γ, IL-4, IL-17 and TGF-β cytokines serum levels were measured at time points of 0, 7 and 14 days. Serum levels of IFN-γ (p = .52) and IL-17 (p = .11) decreased, while IL-4 (p = .12) and TGF-β (p = .14) increased in the nanocurcumin group compared with placebo on day 14. Moreover, gene expressions of TBX21 (p = .02) and FOXP3 (p = .005) genes were significantly decreased and increased between nano-curcumin and placebo groups on day 7, respectively. It can be concluded that administration of nano-curcumin in inflammatory phase of COVID19 can accelerate recovering of the acute..