Dual-Ligand Targeted Nanoparticles Enhance In Vitro Delivery and Efficacy of Investigational Drug Candidate GAT211

We present a dual-ligand polymeric nanoparticle system engineered via coassembly of two distinct ligand-functionalized polymers, one conjugated with gambogic acid (GA) as a targeting ligand, and the other conjugated with naringenin (NAR), which functions dually as a therapeutic agent and targeting ligand. This design enables simultaneous and synergistic targeting of transferrin receptors (TfR) and folate receptors (FR). In vitro studies using fluorescently labeled nanoparticles revealed significantly enhanced cellular uptake and receptor colocalization for dual-ligand nanoparticles compared to their corresponding single-ligand or nontargeted controls. Transwell transport assays modeling intestinal-to-renal epithelial trafficking further confirmed superior transcytosis efficiency. In a cisplatin-induced kidney injury model, dual-ligand nanoparticles loaded with either investigational drug GAT211 or NAR markedly reduced inflammatory markers (TLR4, NF-κB p65, IL-1β, and Bcl2) and improved cell viability, outperforming both unformulated drugs and single-ligand formulations. These findings highlight the synergistic receptor-mediated transport facilitated by GA and NAR, positioning this dual-ligand nanoparticle system as a promising platform for targeted oral drug delivery and laying a strong foundation for subsequent in vivo validation and clinical translation.