Renal tubule-targeted biomimetic nanodrugs achieve precise AKI treatment by halting pro-inflammatory crosstalk between proximal tubular epithelial cells and macrophages

Acute kidney injury (AKI) is a critical clinical disorder characterized by high incidence, high mortality, and numerous complications. However, current supportive therapies cannot reverse established injury, leading to poor outcomes in some patients, and thus, necessitating the development of active therapeutic strategies. Here, we analyzed a clinical single-nucleus RNA sequencing dataset and found that a pathological feedback loop between injured proximal tubular epithelial cells (PTECs) and macrophages drives AKI progression. To simultaneously target this maladaptive crosstalk, we developed N@CM2c, a biomimetic nanodrug composed of NAD⁺ and CCR2-enriched M2c macrophage membranes. The nanoparticle actively targets injured tubules via CCL2 chemotaxis. N@CM2c replenishes the NAD + pool in PTECs and upregulates HAO2 expression to improve fatty acid metabolism, thereby promoting mitochondrial repair while attenuating the inflammatory cascade, which in turn reduces cytokine-mediated macrophage recruitment and pro-inflammatory induction. Concurrently, the CM2c membrane shell and NAD + jointly promote polarization of macrophages towards a reparative phenotype. In AKI mice, this dual-targeting strategy synergistically terminated the inflammatory feedback loop, restored renal function, and reversed pathological damage. By integrating targeted delivery, metabolic reprogramming, and immunomodulation, N@CM2c presents a promising application to halt AKI progression and promote renal repair.