Artemisinin-Loaded Lipid-Polymer Hybrid Nanoparticles with Amorphous Solid Dispersion/Mesoporous Silica Core for Targeted Delivery to Infected Erythrocytes in Malaria Therapy

Abstract

This study aimed to develop a peptide-functionalized lipid-polymer hybrid nanoparticle (LPHN) system to enhance the solubility, stability, sustained release, and selective uptake of artemisinin in Plasmodium-infected erythrocytes. Artemisinin was first converted into an amorphous/mesoporous silica-based core to improve aqueous solubility and then encapsulated into PLGA-lipid hybrid nanoparticles using a nanoprecipitation approach. An infected-erythrocyte-specific peptide was conjugated to the nanoparticle surface via maleimide-thiol coupling to enable targeted delivery. The formulations were characterized for particle size, polydispersity index (PDI), zeta potential, drug loading, and structural integrity (FTIR and DSC). In-vitro evaluation included release kinetics, cellular uptake, cytotoxicity, hemolysis, and selectivity between infected and healthy red blood cells. The optimized LPHNs exhibited a mean particle size of 132 ± 8 nm, a PDI of 0.18, and a high entrapment efficiency of 82.6%. Following peptide conjugation, particle size increased to approximately 145 nm, and the appearance of an amide-I band at ~1650 cm⁻¹ confirmed successful surface functionalization. The hybrid system demonstrated sustained drug release for up to 48 hours, following Korsmeyer-Peppas kinetics. Targeted LPHNs showed significantly enhanced antimalarial potency (IC₅₀ ≈ 0.35 μM) compared with free artemisinin (IC₅₀ ≈ 1.8 μM), with minimal hemolysis and improved selectivity toward infected erythrocytes. The integrated amorphous/mesoporous solubility-enhancement approach combined with peptide-functionalized lipid-polymer hybrid nanoparticles improved sustained release, intracellular delivery, and antimalarial selectivity, highlighting the potential of multifunctional nanocarriers for malaria therapy. The peptide-functionalized LPHN system improved artemisinin solubility, sustained release, and selective uptake in infected erythrocytes, resulting in enhanced antimalarial efficacy with low toxicity and demonstrating promise for targeted malaria treatment.