Ginger phytochemical corona enhances hemocompatibility of metal oxide nanoparticles for blood-contacting applications

Abstract The clinical translation of metal oxide nanoparticles is critically dependent on their hemocompatibility. While chemical synthesis often yields reactive nanoparticles that adversely interact with blood components, green synthesis using plant extracts offers a promising alternative. This study compares the hemocompatibility of four metal oxide nanoparticles (TiO 2 , ZnO, MgO, and CaO) synthesized via conventional chemical precipitation and green synthesis using ginger ( Zingiber officinale ) extract. Ginger-mediated metal oxide nanoparticles formed a stable phytochemical corona, confirmed by FTIR and total phenolic content analysis (106.4 mg GAE/g in extract; 10.6–53.2 mg GAE/g bound to GMONPs). Dynamic light scattering revealed dramatically thinner protein coronas on green metal oxide nanoparticles (hard corona: 10–14 nm vs. 30–97 nm for chemical metal oxide nanoparticles), with ZnO-Ginger showing an 88% reduction ( p  < 0.001). SDS-PAGE demonstrated selective apolipoprotein A-I enrichment (3- to 8-fold) and reduced opsonin adsorption (87–91%) on green metal oxide nanoparticles. ROS quantification confirmed 55–81% reduction in oxidative stress, strongly correlating with hemolysis and PBMC viability. Green metal oxide nanoparticles were consistently non-hemolytic (< 2% vs. 8–18% for chemical metal oxide nanoparticles), preserved normal RBC morphology (> 92% discocytes), maintained PBMC viability > 93% at 500 µg/mL (vs. 68–78%), and showed neutral coagulation for ZnO-Ginger and MgO-Ginger. The safe concentration window expanded from < 125 µg/mL (chemical) to > 500 µg/mL (green). ZnO-Ginger NPs showed the most dramatic improvement: 88% corona reduction, 81% ROS reduction, 93% hemolysis reduction (18% → 1.2%), and > 2.7× IC 50 increase (185 → >500 µg/mL), attributed to the highest phenolic loading (53.2 mg GAE/g) and ApoA-I enrichment (7.8-fold). Ginger extract is a highly effective green agent for producing hemocompatible metal oxide nanoparticles through four protective mechanisms: physical barrier, ion chelation, ROS scavenging, and stealth corona formation. This approach supports their potential use in blood-contacting biomedical applications.