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

Abstract

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.

References

  1. 1.

    Hu CMJ, Fang RH, Zhang LF. Erythrocyte-inspired delivery systems. Adv Healthc Mater. 2012;1:537–47.

    CAS  PubMed  Google Scholar 

  2. 2.

    Mohandas N, Gallagher PG. Red cell membrane: past, present, and future. Blood. 2008;112:3939–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Sheng Y, Liu CS, Yuan Y, Tao XY, Yang F, Shan XQ, et al. Long-circulating polymeric nanoparticles bearing a combinatorial coating of PEG and water-soluble chitosan. Biomaterials. 2009;30:2340–8.

    CAS  PubMed  Google Scholar 

  4. 4.

    Chambers E, Mitragotri S. Prolonged circulation of large polymeric nanoparticles by non-covalent adsorption on erythrocytes. J Control Release. 2004;100:111–9.

    CAS  PubMed  Google Scholar 

  5. 5.

    Yoo JW, Chambers E, Mitragotri S. Factors that control the circulation time of nanoparticles in blood: challenges, solutions and future prospects. Curr Pharm Des. 2010;16:2298–307.

    CAS  PubMed  Google Scholar 

  6. 6.

    Schipper ML, Iyer G, Koh AL, Cheng Z, Ebenstein Y, Aharoni A, et al. Particle size, surface coating, and PEGylation influence the biodistribution of quantum dots in living mice. Small. 2009;5:126–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Hoshyar N, Gray S, Han HB, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine. 2016;11:673–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Albanese A, Tang PS, Chan WC. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng. 2012;14:1–16.

    CAS  PubMed  Google Scholar 

  9. 9.

    Pan D, Vargas-Morales O, Zern B, Anselmo AC, Gupta V, Zakrewsky M, et al. The effect of polymeric nanoparticles on biocompatibility of carrier red blood cells. PLoS One. 2016;11:e152074.

    Google Scholar 

  10. 10.

    Toy R, Hayden E, Shoup C, Baskaran H, Karathanasis E. The effects of particle size, density and shape on margination of nanoparticles in microcirculation. Nanotechnology. 2011;22:115101.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Ta HT, Truong NP, Whittaker AK, Davis TP, Peter K. The effects of particle size, shape, density and flow characteristics on particle margination to vascular walls in cardiovascular diseases. Expert Opin Drug Deliv. 2018;15:33–45.

    CAS  PubMed  Google Scholar 

  12. 12.

    Magnani M, Pierigè F, Rossi L. Erythrocytes as a novel delivery vehicle for biologics: from enzymes to nucleic acid-based therapeutics. Ther Deliv. 2012;3:405–14.

    CAS  PubMed  Google Scholar 

  13. 13.

    Brahler M, Georgieva R, Buske N, Muller A, Muller S, Pinkernelle J, et al. Magnetite-loaded carrier erythrocytes as contrast agents for magnetic resonance imaging. Nano Lett. 2006;6:2505–9.

    CAS  PubMed  Google Scholar 

  14. 14.

    Muzykantov VR. Drug delivery by red blood cells: vascular carriers designed by mother nature. Expert Opin Drug Deliv. 2010;7:403–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chambers E, Mitragotri S. Long circulating nanoparticles via adhesion on red blood cells: mechanism and extended circulation. Exp Biol Med. 2007;232:958.

    CAS  Google Scholar 

  16. 16.

    Sahoo K, Koralege RSH, Flynn N, Koteeswaran S, Clark P, Hartson S, et al. Nanoparticle attachment to erythrocyte via the glycophorin A targeted ERY1 ligand enhances binding without impacting cellular function. Pharmacol Res. 2016;33:1191–203.

    CAS  Google Scholar 

  17. 17.

    Fu Y, Liu W, Wang LY, Zhu BY, Qu MK, Yang LQ, et al. Erythrocyte-membrane-camouflaged nanoplatform for intravenous glucose-responsive insulin delivery. Adv Funct Mater. 2018;28:1802250.

    Google Scholar 

  18. 18.

    Villa CH, Anselmo AC, Mitragotri S, Muzykantov V. Red blood cells: supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems. Adv Drug Deliv Rev. 2016;106:88–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Jensen FB. The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow. J Exp Biol. 2009;212:3387–93.

    CAS  PubMed  Google Scholar 

  20. 20.

    Hamidi M, Zarrin A, Foroozesh M, Mohammadi-Samani S. Applications of carrier erythrocytes in delivery of biopharmaceuticals. J Control Release. 2007;118:145–60.

    CAS  PubMed  Google Scholar 

  21. 21.

    Rossi L, Pierige F, Antonelli A, Bigini N, Gabucci C, Peiretti E, et al. Engineering erythrocytes for the modulation of drugs’ and contrasting agents’ pharmacokinetics and biodistribution. Adv Drug Deliv Rev. 2016;106:73–87.

    CAS  PubMed  Google Scholar 

  22. 22.

    He HN, Ye JX, Wang YS, Liu Q, Chung HS, Kwon YM, et al. Cell-penetrating peptides meditated encapsulation of protein therapeutics into intact red blood cells and its application. J Control Release. 2014;176:123–32.

    CAS  PubMed  Google Scholar 

  23. 23.

    Villa CH, Pan DC, Zaitsev S, Cines DB, Siegel DL, Muzykantov VR. Delivery of drugs bound to erythrocytes: new avenues for an old intravascular carrier. Ther Deliv. 2015;6:795–826.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bird J, Best R, Lewis DA. The encapsulation of insulin in erythrocytes. J Pharm Pharmacol. 1983;35:246–7.

    CAS  PubMed  Google Scholar 

  25. 25.

    Harisa G, Ibrahim MF, Alanazi FK. Characterization of human erythrocytes as potential carrier for pravastatin: an in vitro study. Int J Med Sci. 2011;8:222–30.

    CAS  PubMed Central  Google Scholar 

  26. 26.

    Beutler E, Dale GL, Guinto E, Kuhl W. Enzyme replacement therapy in Gaucher’s disease preliminary clinical trial of a new enzyme preparation. Proc Natl Acad Sci USA. 1977;74:4620–3.

    CAS  PubMed  Google Scholar 

  27. 27.

    Baysal SH, Uslan AH, Pala HH, Tuncoku O. Encapsulation of PEG-Urease/PEG-AlaDH within sheep erythrocytes and determination of the system’s activity in lowering blood levels of urea in animal models. Artif Cells Blood Substit Immobil Biotechnol. 2007;35:391–403.

    CAS  PubMed  Google Scholar 

  28. 28.

    Millan CG, Castaneda AZ, Marinero MLS, Lanao JM. Factors associated with the performance of carrier erythrocytes obtained by hypotonic dialysis. Blood Cells Mol Dis. 2004;33:132–40.

    Google Scholar 

  29. 29.

    Bax BE, Bain MD, Fairbanks LD, Webster ADB, Chalmers RA. In vitro and in vivo studies with human carrier erythrocytes loaded with polyethylene glycol-conjugated and native adenosine deaminase. Br J Haematol. 2000;109:549–54.

    CAS  PubMed  Google Scholar 

  30. 30.

    Banz A, Cremel M, Rembert A, Godfrin Y. In situ targeting of dendritic cells by antigen-loaded red blood cells: A novel approach to cancer immunotherapy. Vaccine. 2010;28:2965–72.

    CAS  PubMed  Google Scholar 

  31. 31.

    Wang GP, Guan YS, Jin XR, Jiang SS, Lu ZJ, Wu Y, et al. Development of novel 5-fluorouracil carrier erythrocyte with pharmacokinetics and potent antitumor activity in mice bearing malignant ascites. J Gastroenterol Hepatol. 2010;25:985–90.

    CAS  PubMed  Google Scholar 

  32. 32.

    Gallagher PG, Chang SH, Rettig MP, Neely JE, Hillery CA, Smith BD, et al. Altered erythrocyte endothelial adherence and membrane phospholipid asymmetry in hereditary hydrocytosis. Blood. 2003;101:4625–7.

    CAS  PubMed  Google Scholar 

  33. 33.

    Podsiedlik M, Markowicz-Piasecka M, Sikora J. Erythrocytes as model cells for biocompatibility assessment, cytotoxicity screening of xenobiotics and drug delivery. Chem Biol Interact. 2020;332:109305.

    CAS  PubMed  Google Scholar 

  34. 34.

    Villa CH, Cines DB, Siegel DL, Muzykantov V. Erythrocytes as carriers for drug delivery in blood transfusion and beyond. Transfus Med Rev. 2017;31:26–35.

    PubMed  Google Scholar 

  35. 35.

    Gao XL, Yue TT, Tian FL, Liu ZP, Zhang XR. Erythrocyte membrane skeleton inhibits nanoparticle endocytosis. AIP Adv. 2017;7:65303.

    Google Scholar 

  36. 36.

    Zhao ZM, Ukidve A, Gao YS, Kim J, Mitragotri S. Erythrocyte leveraged chemotherapy (ELeCt): nanoparticle assembly on erythrocyte surface to combat lung metastasis. Sci Adv. 2019;5:eaax9250.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Pishesha N, Bilate AM, Wibowo MC, Huang NJ, Li ZY, Dhesycka R, et al. Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease. Proc Natl Acad Sci USA. 2017;114:3157–62.

    CAS  PubMed  Google Scholar 

  38. 38.

    Glassman PM, Villa CH, Ukidve A, Zhao ZM, Smith P, Mitragotri S, et al. Vascular drug delivery using carrier red blood cells: focus on RBC surface loading and pharmacokinetics. Pharmaceutics. 2020;12:440.

    CAS  PubMed Central  Google Scholar 

  39. 39.

    Han X, Wang C, Liu Z. Red blood cells as smart delivery systems. Bioconjug Chem. 2018;29:852–60.

    CAS  PubMed  Google Scholar 

  40. 40.

    Yan JJ, Yu JC, Wang C, Gu Z. Red blood cells for drug delivery. Small Methods. 2017;1:1700270.

    Google Scholar 

  41. 41.

    Zaitsev S, Danielyan K, Murciano JC, Ganguly K, Krasik T, Taylor RP, et al. Human complement receptor type 1–directed loading of tissue plasminogen activator on circulating erythrocytes for prophylactic fibrinolysis. Blood. 2006;108:1895–902.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zaitsev S, Spitzer D, Murciano JC, Ding BS, Tliba S, Kowalska MA, et al. Targeting of a mutant plasminogen activator to circulating red blood cells for prophylactic fibrinolysis. J Pharmacol Exp Ther. 2010;332:1022–31.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Domenech C, Thomas X, Chabaud S, Baruchel A, Gueyffier F, Mazingue F, et al. l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011;153:58–65.

    CAS  PubMed  Google Scholar 

  44. 44.

    Anselmo AC, Kumar S, Gupta V, Pearce AM, Ragusa A, Muzykantov V, et al. Exploiting shape, cellular-hitchhiking and antibodies to target nanoparticles to lung endothelium: Synergy between physical, chemical and biological approaches. Biomaterials. 2015;68:1–8.

    CAS  PubMed  Google Scholar 

  45. 45.

    Brenner JS, Pan DC, Myerson JW, Marcos-Contreras OA, Villa CH, Patel P, et al. Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude. Nat Commun. 2018;9:2684.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Red Blood Cells Harnessed as Nanoparticle Carriers for Vaccines. Genetic Engineering and Biotechnology News. 2020 July 14. https://www.genengnews.com/news/red-blood-cells-harnessed-as-nanoparticle-carriers-for-vaccines/

  47. 47.

    Ukidve A, Zhao ZM, Fehnel A, Krishnan V, Pan DIC, Gao YS, et al. Erythrocyte-driven immunization via biomimicry of their natural antigen-presenting function. Proc Natl Acad Sci USA. 2020;117:17727–36.

    CAS  PubMed  Google Scholar 

  48. 48.

    Anselmo AC, Gupta V, Zern BJ, Pan D, Zakrewsky M, Muzykantov V, et al. Delivering nanoparticles to lungs while avoiding liver and spleen through adsorption on red blood cells. ACS Nano. 2013;7:11129–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Zelepukin IV, Yaremenko AV, Shipunova VO, Babenyshev AV, Balalaeva IV, Nikitin PI, et al. Nanoparticle-based drug delivery via RBC-hitchhiking for the inhibition of lung metastases growth. Nanoscale. 2019;11:1636–46.

    CAS  PubMed  Google Scholar 

  50. 50.

    Scott MD, Murad KL, Koumpouras F, Talbot M, Eaton JW, et al. Chemical camouflage of antigenic determinants: Stealth erythrocytes. Proc Natl Acad Sci USA. 1997;14:7566–71.

    Google Scholar 

  51. 51.

    Park J, Andrade B, Seo Y, Kim MJ, Zimmerman SC, Kong H. Engineering the surface of therapeutic “living”cells. Chem Rev. 2018;118:1664–90.

    CAS  PubMed  Google Scholar 

  52. 52.

    Pan DC, Myerson JW, Brenner JS, Patel PN, Anselmo AC, Mitragotri S, et al. Nanoparticle properties modulate their attachment and effect on carrier red blood cells. Sci Rep. 2018;8:1615.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Setyawati MI, Tay CY, Docter D, Stauber RH, Leong DT. Understanding and exploiting nanoparticles’ intimacy with the blood vessel and blood. Chem Soc Rev. 2015;44:8174–99.

    CAS  PubMed  Google Scholar 

  54. 54.

    Barshtein G, Livshits L, Shvartsman LD, Shlomai NO, Arbell D, Yedgar S. Polystyrene nanoparticles activate erythrocyte aggregation and adhesion to endothelial cells. Cell Biochem Biophys. 2016;74:19–27.

    CAS  PubMed  Google Scholar 

  55. 55.

    Charoenphol P, Onyskiw PJ, Carrasco-Teja M, Eniola-Adefeso O. Particle-cell dynamics in human blood flow: Implications for vascular-targeted drug delivery. J Biomech. 2012;45:2822–8.

    PubMed  Google Scholar 

  56. 56.

    Down LA, Papavassiliou DV, O’Rear EA. Significance of extensional stresses to red blood cell lysis in a shearing flow. Ann Biomed Eng. 2011;39:1632–42.

    PubMed  Google Scholar 

  57. 57.

    Chinol M, Casalini P, Maggiolo M, Canevari S, Omodeo ES, Caliceti P, et al. Biochemical modifications of avidin improve pharmacokinetics and biodistribution, and reduce immunogenicity. Br J Cancer. 1998;78:189–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Stephan MT, Irvine DJ. Enhancing cell therapies from the outside in: Cell surface engineering using synthetic nanomaterials. Nano Today. 2011;6:309–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Anselmo AC, Mitragotri S. Cell-mediated delivery of nanoparticles: Taking advantage of circulatory cells to target nanoparticles. J Control Release. 2014;190:531–41.

    CAS  PubMed  Google Scholar 

  60. 60.

    Anselmo AC, Kumar S, Gupta V, Pearce AM, Ragusa A, Muzykantov V, et al. Exploiting shape, cellular-hitchhiking and antibodies to target nanoparticles to lung endothelium: synergy between physical, chemical and biological approaches. Biomaterials. 2015;68:1–8.

    CAS  PubMed  Google Scholar 

  61. 61.

    He CB, Hu YP, Yin LC, Tang C, Yin CH. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31:3657–66.

    CAS  PubMed  Google Scholar 

  62. 62.

    Foged C, Brodin B, Frokjaer S, Sundblad A. Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int J Pharm. 2005;298:315–22.

    CAS  PubMed  Google Scholar 

  63. 63.

    Kulkarni SA, Feng SS. Effects of particle size and surface modification on cellular uptake and biodistribution of polymeric nanoparticles for drug delivery. Pharmacol Res. 2013;30:2512–22.

    CAS  Google Scholar 

  64. 64.

    Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev. 2009;61:428–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Xiao K, Li YP, Luo JT, Lee JS, Xiao WW, Gonik AM, et al. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011;32:3435–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Benne N, van Duijn J, Kuiper J, Jiskoot W, Slutter B. Orchestrating immune responses: How size, shape and rigidity affect the immunogenicity of particulate vaccines. J Control Release. 2016;234:124–34.

    CAS  PubMed  Google Scholar 

  67. 67.

    Nowak M, Brown TD, Graham A, Helgeson ME, Mitragotri S. Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow. Bioeng Transl Med. 2020;5:e10153.

    CAS  PubMed  Google Scholar 

  68. 68.

    Kolhar P, Anselmo AC, Gupta V, Pant K, Prabhakarpandian B, Ruoslahti E, et al. Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proc Natl Acad Sci USA. 2013;110:10753–8.

    CAS  PubMed  Google Scholar 

  69. 69.

    Doshi N, Prabhakarpandian B, Rea-Ramsey A, Pant K, Sundaram S, Mitragotri S. Flow and adhesion of drug carriers in blood vessels depend on their shape: a study using model synthetic microvascular networks. Release. J Control Release. 2010;146:196–200.

    CAS  PubMed  Google Scholar 

  70. 70.

    Lee S, Ferrari M, Decuzzi P. Shaping nano-/micro-particles for enhanced vascular interaction in laminar flows. Nanotechnology. 2009;20:495101.

    PubMed  Google Scholar 

  71. 71.

    Shuvaev VV, Ilies MA, Simone E, Zaitsev S, Kim Y, Cai SS, et al. Endothelial targeting of antibody-decorated polymeric filomicelles. ACS Nano. 2011;5:6991–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Geng Y, Dalhaimer P, Cai SS, Tsai R, Tewari M, Minko T, et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol. 2007;2:249–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Yoo J, Mitragotri S. Polymer particles that switch shape in response to a stimulus. Proc Natl Acad Sci USA. 2010;107:11205–10.

    CAS  PubMed  Google Scholar 

  74. 74.

    Champion JA, Mitragotri S. Shape induced inhibition of phagocytosis of polymer particles. Pharmacol Res. 2009;26:244–9.

    CAS  Google Scholar 

  75. 75.

    Gutierrez M, Ojeda LS, Eniola-Adefeso O. Vascular-targeted particle binding efficacy in the presence of rigid red blood cells: implications for performance in diseased blood. Biomicrofluidics. 2018;12:42217.

    Google Scholar 

  76. 76.

    Anselmo AC, Zhang M, Kumar S, Vogus DR, Menegatti S, Helgeson ME, et al. Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting. ACS Nano. 2015;9:3169–77.

    CAS  PubMed  Google Scholar 

  77. 77.

    Hui Y, Yi X, Wibowo D, Yang GZ, Middelberg APJ, Gao HJ, et al. Nanoparticle elasticity regulates phagocytosis and cancer cell uptake. Sci Adv. 2020;6:eaaz4316.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Guo P, Liu D, Subramanyam K, Wang BR, Yang J, Huang J, et al. Nanoparticle elasticity directs tumor uptake. Nat Commun. 2018;9:130.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA. 2006;103:4930–4.

    CAS  PubMed  Google Scholar 

  80. 80.

    Anselmo AC, Mitragotri S. Impact of particle elasticity on particle-based drug delivery systems. Adv Drug Deliv Rev. 2017;108:51–67.

    CAS  PubMed  Google Scholar 

  81. 81.

    Herant M. Mechanics of neutrophil phagocytosis: behavior of the cortical tension. J Cell Sci. 2005;118:1789–97.

    CAS  PubMed  Google Scholar 

  82. 82.

    Garapaty A, Champion JA. Tunable particles alter macrophage uptake based on combinatorial effects of physical properties. Bioeng Transl Med. 2017;2:92–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Carboni E, Tschudi K, Nam J, Lu XL, Ma AWK. Particle margination and its implications on intravenous anticancer drug delivery. AAPS PharmSciTech. 2014;15:762–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Gupta N, Kozlovskaya V, Dolmat M, Kharlampieva E. Shape recovery of spherical hydrogen-bonded multilayer capsules after osmotically induced deformation. Langmuir. 2019;35:10910–9.

    CAS  PubMed  Google Scholar 

  85. 85.

    Zhao YN, Sun XX, Zhang GN, Trewyn BG, Slowing II, Lin VSY. Interaction of mesoporous silica nanoparticles with human red blood cell membranes: size and surface effects. ACS Nano. 2011;5:1366–75.

    CAS  PubMed  Google Scholar 

  86. 86.

    Muzykantov VR, Taylor RP. Attachment of biotinylated antibody to red blood cellsantigen-binding capacity of immunoerythrocytes and their susceptibility to lysis by complement. Anal Biochem. 1994;1:142–8.

    Google Scholar 

  87. 87.

    Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med. 2010;16:1035–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Arruebo M, Valladares M, González-Fernández Á. Antibody-conjugated nanoparticles for biomedical applications. J Nanomater. 2009;2009:439389.

    Google Scholar 

  89. 89.

    Zhou H, Fan Z, Li PY, Deng JJ, Arhontoulis DC, Li CY, et al. Dense and dynamic polyethylene glycol shells cloak nanoparticles from uptake by liver endothelial cells for long blood circulation. ACS Nano. 2018;12:10130–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Ishida T, Maeda R, Ichihara M, Irimura K, Kiwada H. Accelerated clearance of PEGylated liposomes in rats after repeated injections. J Control Release. 2003;88:35–42.

    CAS  PubMed  Google Scholar 

  91. 91.

    Hall SS, Mitragotri S, Daugherty PS. Identification of peptide ligands facilitating nanoparticle attachment to erythrocytes. Biotechnol Prog. 2007;23:749–54.

    CAS  PubMed  Google Scholar 

  92. 92.

    Lindorfe MA, Hahn CS, Foley PL, Taylor RP. Heteropolymer-mediated clearance of immune complexes via erythrocyte CR1 mechanisms and applications. Immunol Rev. 2001;183:10–24.

    Google Scholar 

  93. 93.

    Zaitsev S, Spitzer D, Murciano J, Ding BS, Tliba S, Kowalska MA, et al. Sustained thromboprophylaxis mediated by an RBC-targeted pro-urokinase zymogen activated at the site of clot formation. Blood. 2010;115:5241–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Potempa M, Potempa J. Protease-dependent mechanisms of complement evasion by bacterial pathogens. Biol Chem. 2012;393:873–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Fang RH, Hu CJ, Chen KNH, Luk BT, Carpenter CW, Gao WW, et al. Lipid-insertion enables targeting functionalization of erythrocyte membrane-cloaked nanoparticles. Nanoscale. 2013;5:8884–8.

    CAS  PubMed  Google Scholar 

  96. 96.

    Shi G, Mukthavaram R, Kesari S, Simberg D. Distearoyl anchor-painted erythrocytes with prolonged ligand retention and circulation properties in vivo. Adv Healthc Mater. 2014;3:142–8.

    CAS  PubMed  Google Scholar 

  97. 97.

    Mukthavaram R, Shi G, Kesari S, Simberg D. Targeting and depletion of circulating leukocytes and cancer cells by lipophilic antibody-modified erythrocytes. J Control Release. 2014;183:146–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Reist CJ, Combs MJ, Croft BY, Taylor RP. Antigens pre-bound to the primate erythrocyte complement receptor via cross-linked bispecific monoclonal antibody heteropolymers are rapidly cleared from the circulation. Eur J Immunol. 1993;23:3021–7.

    CAS  PubMed  Google Scholar 

  99. 99.

    Zhu DM, Wu L, Suo M, Gao S, Xie W, Zan MH, et al. Engineered red blood cells for capturing circulating tumor cells with high performance. Nanoscale. 2018;10:6014–23.

    CAS  PubMed  Google Scholar 

  100. 100.

    Tzounakas VL, Karadimas DG, Papassideri IS, Seghatchian J, Antonelou MH. Erythrocyte-based drug delivery in Transfusion Medicine: Wandering questions seeking answers. Transfus Apher Sci. 2017;56:626–34.

    PubMed  Google Scholar 

  101. 101.

    Banz A, Cremel M, Mouvant A, Guerin N, Horand F, Godfrin Y. Tumor growth control using red blood cells as the antigen delivery system and poly(I:C). J Immunother. 2012;35:409–17.

    CAS  PubMed  Google Scholar 

  102. 102.

    Gao WW, Zhang LF. Engineering red‐blood‐cell‐membrane–coated nanoparticles for broad biomedical applications. AIChE J. 2015;61:738–46.

    CAS  Google Scholar 

  103. 103.

    Murad KT, Mahany KL, Brugnara C, Kuypers FA, Eaton JW, Scott ML. Structural and functional consequences of antigenic modulation of red blood cells. Blood. 1999;93:2121–7.

    CAS  PubMed  Google Scholar 

  104. 104.

    Tan YX, Qiu Y, Xu H, Ji SP, Li SB, Gong F, et al. Decreased immunorejection in unmatched blood transfusions by attachment of methoxypolyethylene glycol on human red blood cells and the effect on D antigen. Transfusion. 2006;46:2122–7.

    CAS  PubMed  Google Scholar 

  105. 105.

    Nacharaju P, Boctor FN, Manjula BN, Acharya SA. Surface decoration of red blood cells with maleimidophenyl-polyethylene glycol facilitated by thiolation with iminothiolane: an approach to mask A, B, and D antigens to generate universal red blood cells. Transfusion. 2005;45:374–83.

    CAS  PubMed  Google Scholar 

  106. 106.

    Sarvi F, Najafabadi SH, Farahani EV, Shojaosadati SA. Surface coating of red blood cells with monomethoxy poly(ethylene glycol) activated with two different reagents. Iran J Chem Chem Eng-Int Engl Ed. 2008;27:1–9.

    CAS  Google Scholar 

  107. 107.

    Bourgeaux V, Lanao JM, Bax BE, Godfrin YL. Drug-loaded erythrocytes: on the road toward marketing approval. Drug Des Devel Ther. 2016;10:665–76.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/s41401-020-00606-z

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Keyword

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

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