Surface Functionalization of PLGA Nanoparticles with Hyaluronic Acid of Different Molecular Weight for Targeted Drug Delivery to Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a severe renal condition characterized by an abrupt decline in kidney function. Poly(Lactide-co-Glycolide) (PLGA) is a well-known biocompatible polymer widely investigated for nanoparticle carrier systems; however, it faces challenges with non-specific distribution and AKI targeting. In this study, a targeted drug delivery system was developed by using functionalized PLGA nanoparticles with HA to enhance therapeutic delivery efficiency to injured kidneys overexpressing CD44. PLGA nanoparticles were synthesized using a double emulsion (W/O/W) method and subsequently functionalized with thiol groups via cysteamine conjugation. Maleimide-functionalized hyaluronic acid (HA-Mal) of varying molecular weights (200 kDa, 500 kDa, and 3 MDa) were synthesized and conjugated to the nanoparticles through a thiol-maleimide click reaction. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) confirmed spherical morphology and increased hydrodynamic size post-functionalization. Angiotensin 1-7, a therapeutic peptide with anti-inflammatory and renoprotective properties, was encapsulated within the nanoparticles, exhibiting sustained release profiles and high encapsulation efficiency. Cellular uptake studies validated the selectivity of HA-coated nanoparticles for CD44-overexpressing cells. These findings demonstrate the potential of HA-functionalized PLGA nanoparticles as a kidney-specific drug delivery platform, providing a promising approach to enhancing AKI treatment with minimized side effects.