Lysozyme-Targeted Liposomes for Enhanced Tubular Targeting in the Treatment of Acute Kidney Injury.

Abstract

Acute kidney injury (AKI) is defined by the release of pro-inflammatory factors, leading to structural damage in renal tubules and subsequent tubular cell injury and death. Delivering drugs specifically to renal tubules to mitigate tubular cell damage holds potential for AKI treatment. In this work, we developed functional liposomes (LZM-PLNPs-TP) designed to bypass the glomerular filtration barrier and target tubules by leveraging the unique structural and pathological characteristics of glomeruli and tubules. LZM-PLNPs-TP, incorporating lysozyme (LZM) and cationic liposome, and carrying the anti-inflammatory and antioxidant drug Triptolide (TP), demonstrated favorable stability, efficient drug release, and good cytocompatibility in wide TP concentrations (0-100 ng/mL). These liposomes exhibited the enhanced renal accumulation, tubular retention, and cellular targeting through endocytosis by peritubular capillary endothelial cells. The administration of LZM-PLNPs-TP at a minimal TP dosage (0.01 mg/kg) demonstrated significant protection through the mitigation of oxidative stress and inflammation in ischemia/reperfusion injury (IRI) mice, while the naked TP (0.01 mg/kg) exhibited lower efficacy. Following treatment with LZM-PLNPs-TP, levels of serum creatine, blood urea nitrogen, superoxide dismutase, malondialdehyde, as well as the inflammatory cytokines IL-1β and IL-6 in renal IRI mice were found to be significantly reduced by factors of 2.9, 1.7, 0.7, 1.3, 2.1, and 1.9, respectively, compared to mice treated with TP alone. In summary, this study presents an LZM-targeted drug delivery system that synergistically enhances tubular reabsorption and cellular uptake, offering a promising strategy for AKI treatment. STATEMENT OF SIGNIFICANCE: We have designed specialized liposomes (LZM-PLNPs-TP) with targeting capabilities towards renal tubules to enhance cellular internalization, offering a promising therapeutic strategy for AKI treatment. Our research confirms that the increased accumulation of LZM-PLNPs-TP in renal tubules is facilitated by peritubular capillary endothelial cells rather than glomerular filtration. LZM-PLNPs-TP demonstrated effective mitigation of oxidative stress, inflammation suppression, and significant improvement in kidney injury, ultimately leading to the restoration of renal function in murine models of AKI induced by ischemia/reperfusion. This study introduces LZM-targeted liposomes that enhance tubular reabsorption and cellular uptake synergistically, providing a promising therapeutic approach for AKI management.