Halting the Progression of Acute Kidney Injury: A Tubular‐Inspired Reusable Detoxifier Against Protein‐Bound Uremic Toxins and Oxidative Stress

ABSTRACT Renal dysfunction such as acute kidney injury leads to systemic metabolite retention, and protein‐bound uremic toxins (PBUTs) serve as critical contributors to the accelerated progression of renal disease. Their strong albumin binding hinders clearance via blood purification in patients with kidney disease, leading to accumulation that promotes oxidative stress and other complications. These symptoms will simultaneously aggravate the progression of kidney diseases, creating a vicious cycle. Inspired by the intrinsic “dissociation‐transport” mechanism towards PBUTs and the antioxidant functions of proximal tubular epithelial cells in human body, a dual‐functional detoxifier has been developed to mitigate oxidative stress followed by removing PBUTs. By loading danshensu (DS) onto styrenated β‐cyclodextrin‐cationic microspheres (SDCMs) as a binding competitor, this detoxifier possesses an integrated “dissociation‐adsorption” capability. Ingeniously, DS acts as an antioxidant and works with adsorbents to reduce the reactive oxygen species induced by PBUTs, which plays a synergistic role in alleviating oxidative stress in patients. These functions have been validated in both in vitro and in vivo experiments. SDCMs serve as a reusable adsorbent substrate, retaining over 95% regeneration efficiency after five adsorption‐desorption cycles in albumin solution. In hemoperfusion of renal injury rabbit models, SDCMs–DS achieved superior clearance rates for typical PBUTs (49.79% for hippuric acid, 38.47% for p‐cresyl sulfate, and 50.67% for indoxyl sulfate) compared to the commercial adsorbent HA 130 (38.21%, 24.25%, and 41.18%, respectively). Concurrently, SDCMs–DS mitigates oxidative stress, suppresses inflammation, and apoptosis. This multi‐target protective strategy demonstrates substantial clinical potential for renal injury management.