Despite extensive studies on different types of nanoparticles as potential drug carriers, the application of red blood cells (RBCs) as natural transport agents for systemic drug delivery is considered a new paradigm in modern medicine and possesses great potential. There is a lack of studies on the influence of drug carriers of different compositions on RBCs, especially regarding their potential impact on human health. Here, we apply conventional microscopy to observe the formation of RBC aggregates and optical tweezers to quantitatively assess the mutual interaction of RBCs incubated with inorganic and polymeric nanoparticles. Scanning electron microscopy is utilized for direct observation of nanoparticle localization on RBC membranes. The experiments are performed in a platelet-free blood plasma mimicking the RBC natural environment. We show that nanodiamonds influence mutual RBC interactions more antagonistically than other nanoparticles, resulting in higher aggregation forces and the formation of larger cell aggregates. In contrast, polymeric particles do not cause anomalous RBC aggregation. The results emphasize the application of optical tweezers for the direct quantitative assessment of the mutual interaction of RBCs influenced by nanomaterials.