Nano-safety guardians: Surface engineering strategies for building hemocompatible shields

• We elaborated the critical need for in-depth investigation into the interaction between nanomaterials and blood to comprehensively characterize their blood compatibility, with the aim of developing a nanomedicine delivery system that exhibits superior blood compatibility. • A comprehensive analysis was performed to analyze the correlation between the surface properties of nanoparticles and hemolysis. • We developed a series of 3D illustrations to elucidate the mechanisms by which nanoparticles induce hemolysis. • We proposed a series of preventive measures to reduce or eliminate the hemolytic activity of nanoparticles in this manuscript. • We conducted a comprehensive analysis of the impact of nanoparticle size and dosage on their hemolytic properties, as well as strategies to enhance these properties. Nanoparticles are extensively investigated due to their enhanced solubility, pharmacokinetics, and biodistribution. However, hemolysis caused by nanomedicine delivery systems poses a significant challenge. Nanoparticle-induced hemolysis can result in elevated levels of pro-inflammatory cytokines, complement activation, granulocyte activation, and impaired phagocytic function. Additionally, parameters such as nanoparticle surface charge, size, structure, morphology, and concentration significantly influence the hemolysis rate. To reduce hemolysis rate, biocompatible coatings (such as liposomes, proteins, or polymers) are applied to the nanoparticle surface, and the dosage of nanoparticles is carefully controlled. In this review, we summarize the mechanisms of nanoparticle-induced hemolysis, including direct interaction with red blood cells and membrane disruption. Then we systematically analyze these surface properties and their interactions with blood components to elucidate their impact on hemolysis, emphasize that nanoparticle hemolytic activity is influenced by multiple surface characteristics rather than a single factor. Moreover, physiological environment exhibits a complex and nonlinear relationship with hemolytic activity, potentially affecting it indirectly through changes in nanoparticle surface properties. Finally, we provide an in-depth overview of biocompatible coatings and recommend optimal surface properties and concentrations of nanoparticles to guide material selection. We believe that these insights will contribute to the development of safer and more effective nanomedicine delivery systems.