Repurposing mesalamine for acute kidney injury through supramolecular assembly

Acute kidney injury (AKI) is a prevalent and life-threatening condition, particularly in patients undergoing high-risk surgeries, where the incidence can exceed 50 %. Despite its growing impact, therapeutic options remain limited, with dialysis being the primary treatment. Drug repurposing offers a better risk-versus-reward trade-off for accelerating the development of effective therapies. Mesalamine, a clinically approved anti-inflammatory agent for ulcerative colitis, can be a promising candidate for AKI treatment due to its ability to modulate various inflammatory pathways. However, their risk of nephrotoxicity from systemic exposure underscores the need for strategies to control off-target effects. Here, we propose a mesalamine prodrug, a conjugate between mesalamine and a cathepsin B-cleavable peptide, which spontaneously forms nanoassemblies through intermolecular interactions. In a mouse AKI model, these nanoassemblies accumulate in the inflamed kidney by becoming trapped between disrupted tight junctions, subsequently releasing mesalamine precisely at the site of injured tubular cells to alleviate the disease. Meanwhile, side effects from non-specific drug release are minimized as the nanoassemblies remain inactive in healthy tubular cells and other normal organs with relatively low cathepsin B expression. This study provides valuable insights into a rational approach to facilitating drug repositioning for the effective and safer use of mesalamine in AKI.