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Surface loading of nanoparticles on engineered or natural erythrocytes for prolonged circulation time: strategies and applications


Nano drug-delivery systems (DDS) may significantly improve efficiency and reduce toxicity of loaded drugs, but a few nano-DDS are highly successful in clinical use. Unprotected nanoparticles in blood flow are often quickly cleared, which could limit their circulation time and drug delivery efficiency. Elongating their blood circulation time may improve their delivery efficiency or grant them new therapeutic possibilities. Erythrocytes are abundant endogenous cells in blood and are continuously renewed, with a long life span of 100–120 days. Hence, loading nanoparticles on the surface of erythrocytes to protect the nanoparticles could be highly effective for enhancing their in vivo circulation time. One of the key questions here is how to properly attach nanoparticles on erythrocytes for different purposes and different types of nanoparticles to achieve ideal results. In this review, we describe various methods to attach nanoparticles and drugs to the erythrocyte surface, and discuss the key factors that influence the stability and circulation properties of the erythrocytes-based delivery system in vivo. These data show that using erythrocytes as a host for nanoparticles possesses great potential for further development.

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Fig. 1: The forces acting on nanoparticles under flow.
Fig. 2: The design of antibody-modified fibroblasts (Ab/fibroblasts) and their anchoring mechanism to target endothelial cells in the bloodstream.
Fig. 3: Time-lapse video microscopy clip of the shape-dependent phagocytosis of macrophages.
Fig. 4: Flexible spheres, rigid spheres or rigid rods approaching the cell membrane at different angles, such as vertical or tangential angles, are absorbed by cells with different efficiencies.
Fig. 5: Synergistic contributions to the NP internalization process.
Fig. 6: Attachment of nanoparticles to erythrocytes.
Fig. 7: Some modifications based on covalent binding and ligand-anchoring.
Fig. 8: Coupling of tPA to circulating RBCs reduces rebleeding.
Fig. 9: Methods based on lipid modification on the surface of red blood cells.
Fig. 10: Schematic diagram of the chemical, physical, and biological modifications investigated for RES avoidance and lung targeting.
Fig. 11: Preparation of engineered RBCs.
Fig. 12: Schematic diagram of a series of reactions for camouflaging erythrocytes with poly(ethylene glycol) (PEG) via reaction with erythrocytes surface amines.


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This work was supported by National Natural Science Foundation of China (Nos. 81872824 and 51721091). Sichuan University provided necessary services for the writing of the manuscript.

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Correspondence to Zhi-rong Zhang or Zhen-mi Liu.

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Zhang, Sq., Fu, Q., Zhang, Yj. et al. Surface loading of nanoparticles on engineered or natural erythrocytes for prolonged circulation time: strategies and applications. Acta Pharmacol Sin 42, 1040–1054 (2021).

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  • drug delivery systems
  • nanoparticle
  • erythrocytes
  • prolonged circulation time


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