Engineering polyamidoamine dendrimer nanoparticles for targeted drug delivery to proximal tubular cells after renal ischemia/reperfusion injury

Acute kidney injury (AKI) is a prevalent and potentially severe clinical condition that currently lacks effective therapeutic options. Major obstacles to treatment include the glomerular filtration barrier, which restricts access of many therapeutic agents to injured tubular epithelial cells, and off-target effects of potent drugs on uninvolved organs. Given the susceptibility of proximal tubule (PT) cells to multiple forms of injury, we identified the folate receptor (FOLR1), highly expressed in both LTL-positive healthy and KIM-1-positive injured PT cells, as a potential target for cell-specific drug delivery. We synthesized and characterized folic acid (FA)-conjugated, acetylated polyamidoamine dendrimer [FA-G4(-Ac₁₀)] nanoparticles, which are capable of crossing the glomerular filtration barrier and selectively targeting FOLR1-expressing PT cells. Following intravenous injection, FA-G4(-Ac₁₀) nanoparticles showed a 2.9-fold and 9.1-fold increase in uptake by PT cells compared to FA-G4 and unmodified G4 nanoparticles, respectively. To assess therapeutic efficacy, we loaded the PPARα agonist, Wy-14643, within FA-G4(-Ac₁₀) nanoparticles and administered a single dose to the mice 7 days post-ischemia/reperfusion injury. Treatment significantly upregulated PPARα target gene expression, reduced pro-inflammatory gene expression, and improved renal function in injured kidneys. Our findings demonstrate that FA-conjugated, acetylated dendrimer nanoparticles enable targeted delivery of therapeutic agents to both healthy and injured PT cells and represent a promising strategy for advancing treatment of AKI.