Innovative hyaluronic acid-decorated quatsomes for enhanced renal targeting: design, optimization and in-vivo...

The kidney plays a critical role in metabolite excretion, fluid regulation, and homeostasis, yet remains highly vulnerable to structural and functional disorders. Kidney diseases represent a major global health burden, often progressing to chronic complications due to the limited efficacy and poor selectivity of conventional therapies, which are frequently associated with systemic toxicity. Accordingly, the development of targeted drug delivery systems is essential to improve therapeutic outcomes. In this study, advanced quatsomes were developed as a kidney-targeted nanosystem to enhance the delivery of curcumin, a natural polyphenolic compound with potent antioxidant and nephroprotective properties. The system was composed of di-dodecyl-dimethyl-ammonium bromide (DDAB), cholesterol, limonene, hyaluronic acid (HA) and surfactants, and was fabricated using the ethanol injection method. A 2³ factorial design was employed to optimize formulation variables, including DDAB:cholesterol ratio, limonene:drug ratio, and surfactant concentration. The optimized formulation (desirability = 0.950) exhibited high entrapment efficiency (87.80%), nanosized vesicles (120.55 nm), and a positive surface charge (+38.30 mV). Transmission electron microscopy confirmed spherical morphology, while in-vitro release studies demonstrated a biphasic profile. The formulation also showed good physicochemical stability and enhanced antioxidant activity. Mechanistically, passive targeting via nanoscale size and cationic charge facilitated interaction with the glomerular filtration barrier and mesangial uptake, while limonene improved vesicle deformability. HA functionalization further enabled CD44-mediated active targeting. In vivo, the optimized system significantly reduced serum creatinine and blood urea nitrogen levels in a cisplatin-induced nephrotoxicity model, with histological evidence of renal protection. Overall, the developed quatsomes demonstrate promising potential as an efficient renal-targeted nanocarrier.