# Erythrocytes and Nanoparticles: New Therapeutic Systems
## 2 Bio Hybrid Carrier Using RBC
### NanoerythInosomes (NERs)  
Another nano-system with applications in drug delivery is represented by NERs: small vesicles obtained from erythrocytes that offer additional benefits to the already well-known advantages of RBC-based systems. Because of their reduced size and higher surface-to-volume ratio, they can access locations unreachable for RBCs. They also have  
Figure 1: Scheme representing the preparation of whole red blood cell (RBC) loaded with nanoparticles (NPs) or therapeutic molecules (carrier into carrier), NPs coated with RBC membrane and nano-erythrosomes (NERs).  
prolonged circulation time [33], due to their avoidance of RES clearance [34]. Some authors have remarked that the characteristic shape of RBCs could also play an important role in the reduction of systemic clearance, as has been demonstrated for vesicles obtained from erythrocyte membranes containing anisotropic NPs [35]. Although some changes in their structure have been observed during the formation of NERs [36], they preserve enough similarity with the surface of native erythrocytes to maintain their inherent biocompatibility. Nevertheless, modifications of NERs have been proposed in order to increase vesicle suspension stability and circulation times [36; 37].  
NERs--classified by some authors as a particular type of RBC-mimicking particle [34; 35]--are considered in this review as different nanoparticulated entities, due to their biological origin (in contrast to the synthetic NPs above mentioned).  
Erythrocytes are the main extracellular vesicle producers in blood; in healthy individuals there is a physiological basal level of derived nanovesicles that can be increased under pathological conditions [38]. Nevertheless, these vesicles can also be obtained artificially, and different methods for NER production (e.g., sonication, electrical breakdown, extrusion and their combination) have been proposed.  
As well as carrier erythrocytes, NERs have been studied as carriers of drugs, enzymes and other peptides, toxins, genetic material, contrast agents [39] and even other NPs [35]. They can be applied in drug targeting to the liver, the spleen, lymphatic ganglia and tumors [40].  
NERs have also been proposed for cancer vaccination. NERs loaded with tumor-associated antigens (Nano-Ag@erythrosomes), obtained by fusion of NERs with the membrane of tumor cells, have confirmed their ability to reach splenic antigen-presenting cells and activate T cell immune responses. The administration of nano-Ag@erythrosomes is adjuvant in combination with immune checkpoint blockade (ICB) therapy-induced tumor regression in tumor models [41].  
Combination of NERs with other systems have also been explored. [PERSON] et al. demonstrated the feasibility of an active cargo delivery system designed by conjugation of NERs with genetically engineered peritrichously flagellated _Escherichia coli_ by biotin-streptavidin interaction. These biohybrid micro-swimmers may be used in autonomous targeted cargo delivery applications, allowing (1) faster propulsion than those based in RBCs and (2) access to smaller locations, thanks to the nanosized dimensions of their components [42].