Kidney-Targeted Biomimetic Nanoparticles Loaded With Apolipoprotein H Alleviate Sepsis-Associated Acute Kidney Injury by Inhibiting the TLR4/NF-κB Pathway.

Abstract

Sepsis-associated acute kidney injury (SA-AKI) is a common and life-threatening complication of sepsis, whose high incidence and mortality severely impair patient prognosis. Existing anti-AKI drugs exhibit limited efficacy due to their inability to efficiently target injured kidneys. Although kidney-targeted nanocarrier delivery systems show potential, exogenous nanoparticles are rapidly cleared by the immune system, resulting in a short blood circulatory half-life and unsatisfactory targeting efficiency. Recombinant apolipoprotein H (rAPOH) exhibits anti-apoptotic and anti-inflammatory activities, holding promise for SA-AKI treatment; however, its efficacy is constrained by insufficient targeting capability and rapid in vivo metabolic clearance. In this study, we constructed a biomimetic delivery system (KMA@rAPOH) consisting of A@rAPOH nanoparticles coated with kidney-targeting peptide-functionalized renal tubular epithelial cell membranes to realize targeted rAPOH delivery for SA-AKI therapy. The nanocarrier demonstrated satisfactory encapsulation efficiency, high drug loading capacity, and favorable controlled release, along with excellent long-term stability in DMEM and deionized water. In vitro, KMA@rAPOH was efficiently internalized by renal tubular epithelial cells and exerted significant anti-apoptotic and anti-inflammatory effects. In a mouse model of SA-AKI, KMA@rAPOH markedly alleviated renal pathological damage and inhibited cell apoptosis. Additionally, it reduced the proportion of CD11c⁺F4/80⁺ pro-inflammatory macrophages in the renal CD45⁺CD11b⁺ population. Mechanistically, KMA@rAPOH was found to reduce TLR4 levels and inhibit NF-κB p65 phosphorylation, accompanied by decreased secretion of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. These observations indicate that the TLR4/NF-κB cascade may partially mediate the renoprotective activity of KMA@rAPOH, and this biomimetic nanoplatform represents a promising targeted delivery strategy for the treatment of renal inflammatory disorders.