Pulmonary arterial hypertension (PAH) is a devastating disease driven largely by oxidative stress and inflammation. The pulmonary arterial endothelium plays a key role in PAH pathogenesis. In this study, we developed novel poly(lactic-co-glycolic acid) (PLGA)-based lutein nanoparticles coated with a Vascular Cell Adhesion Molecule-1 (VCAM-1) antibody to target pulmonary arterial endothelial cells (PAECs) associated with PAH. Lutein, a potent antioxidant and anti-inflammatory carotenoid, served as the model drug. The lutein nanoparticles were produced by nanoprecipitation, followed by surface modification with VCAM-1 antibody. Physicochemical characterization and cellular efficacy studies were performed to assess the potential of the formulation. The studies revealed the production of nanoparticles with an average size of approximately 170 nm that exhibited specificity for PAH patient-derived PAECs (PAH-PAECs) and antioxidant and anti-inflammatory properties. Moreover, the nanoparticles did not exhibit significant cellular toxicity toward healthy PAECs. This proof-of-principle study demonstrates the therapeutic potential of targeted nanoparticles for the treatment of PAH.