Several comorbidities of sickle cell disease (SCD) originate from red blood cell (RBC) instability, chronic inflammation, and oxidative stress. Development of scalable, cost-effective therapeutics suitable for chronic administration to prevent, attenuate, and perhaps reverse the consequences of RBC instability is needed. Curcumin has many of these attributes as a safe compound with antisickling, antiinflammatory, and antioxidant properties, but its translational potential has been constrained due to limited bioavailability from oral administration. The present study demonstrates the rapid and high bioavailability of a novel topical/transdermal (TD) curcumin gel formulation in the plasma and blood cells and its effectiveness in humanized sickle cell mice in: (i) ameliorating features of sickle cell pain hypersensitivity and axonal injury
(ii) reducing multiple manifestations of RBC instability including evidence of decreased hemolysis (reduced lactate dehydrogenase levels), enhanced RBC ATP levels along with decreased oxidative damage
(iii) decreasing multiple proinflammatory cytokines including interleukin-6, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and activation, normal T cell expressed and secreted protein in skin secretome
and (iv) reducing mast cell degranulation and activation. Our data suggest that an easy-to-use novel TD curcumin gel formulation has the potential to ameliorate chronic pain, improve RBC stability, and reduce inflammatory consequences of SCD.