Implementation of nanomaterials into modern industries has been occurring at an ever-increasing pace for decades (Kanaoujiya et al., 2023; Malik et al., 2023). Nanotechnology applications in medical and biotechnological fields have transfigured diagnosis and treatment of multiple diseases establishing a novel and rapidly developing branch of medicine called nanomedicine (Jia et al., 2023). Nanotechnology-based innovations pave the way for solutions to a number of major healthcare-related challenges, such as cancer treatment and antimicrobial resistance. Indeed, nanotechnology-based drugs and vaccines (Gildiz and Minko, 2023; Pozharov and Minko, 2023), drug delivery systems (Alimardani et al., 2023; Gomes et al., 2023; Tundisi et al., 2023), and biosensors (Choi and Yoon, 2023; Nasrollahpour et al., 2023) have become a reality. A growing number of studies on nanomaterials-based theranostics, a simultaneous cancer detection and treatment, highlight the potential of nanotechnology in this field of medicine (Choi and Kim, 2023; Kalita and Patowary, 2023; Shailendrakumar and Tippavajhala, 2022). Antibacterial and biofilm-inhibiting properties of nanomaterials suggest that they can come to the rescue in the fight against antimicrobial resistance (Brar et al., 2023; Hetta et al., 2023; Mohanta et al., 2022). However, the number of nanopharmaceuticals approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) remains surprisingly low compared to the discovered, developed and preclinically tested nanomaterials (Anselmo and Mitragotri, 2019; Rodríguez et al., 2022). One of the reasons behind this is the toxicity of nanoscale materials. The full-scale assessment of nanostructured materials safety profiles requires a multitude of studies with numerous crucial toxicological endpoints (Monteiro-Riviere, 2022). Evaluation of redox homeostasis-related effects, cytotoxicity, genotoxicity, epigenetic effects, immunotoxicity, and other nanomaterials-mediated toxic properties should be achieved via a balanced approach combining in silico, in vitro, in vivo and “omics” technologies (Domingues et al., 2022). Nanoscale materials-induced toxicity mechanisms include oxidative stress due to reactive oxygen species (ROS) generation, ROS-mediated DNA damage and cell death (apoptosis, ferroptosis, necroptosis, pyroptosis, autophagy-related cell death, cuproptosis, NETosis, etc.) and immunologic pro-inflammatory effects (Dusinska et al., 2017; Guo et al., 2023; Lebre et al., 2022; Muñoz et al., 2016; Tkachenko et al., 2023; Yang et al., 2021). Toxicity of nanomaterials can be modulated by size, shape, surface features, charge, solubility, coating, doping, the number of atoms in a nanoparticle, and routes of exposure (Ali, 2023). Routes of exposure along with physico-chemical properties determine biodistribution and clearance of nanomaterials. Of note, despite the route of exposure, nanomaterials enter the bloodstream interacting with blood cells, primarily erythrocytes due to their abundance, which suggests that hemocompatibility testing has to be systemic and obligatory in nanotoxicological studies (Fröhlich, 2017). Hemocompatibility studies in nanotoxicology may include evaluation of blood viscosity and blood coagulation, platelet aggregation and activation, erythrocyte deformability, leukocyte functions, and phagocytosis (de la Harpe et al., 2019). In a recent study published by Perugini et al., a multi-step protocol for nanoparticles in vitro hemocompatibility testing is suggested. It includes evaluation of nanoparticles-protein interactions by assessing protein adsorption and depletion, as well as blood coagulation, and nanoparticles-cells interactions by investigating cell lysis, ROS and cytokine production (Perugini et al., 2022). In general, hemolytic assays are widely approved as a cytotoxicity marker for blood compatibility testing of nanomaterials (Yedgar et al., 2022). However, it has been clearly documented in multiple toxicological studies that eryptosis, an apoptosis-like regulated cell death (RCD) of erythrocytes, is more sensitive than hemolysis in evaluating the hemocompatibility of xenobiotics (Farag and Alagawany, 2018; Tkachenko et al., 2023). In this review, we aim at summarizing studies dealing with the impact of nanomaterials on eryptosis, compare nanomaterials-induced eryptosis and hemolysis, highlight the mechanisms underlying the cytotoxicity of nanoscale materials against erythrocytes and eventually provide insights into the feasibility of using eryptosis as a marker of hemocompatibility for nanoparticles.