From blood to brain: blood cell-based biomimetic drug delivery systems

Figures & data

Figure 1. Different types of blood-cell based vehicles for brain drug delivery.

Table 1. Summary of blood cell-based vehicles for brain drug delivery.

Source of blood cells	Vehicles	Cargo	Strategies	Brain disease and model	Key advances	Ref.
Erythrocyte	Erythrocyte membrane	Dox-loaded PLGA nanoparticles	Neurotoxin-derived peptide for brain targeting Erythrocyte membrane for long circulation DOX-PLGA for drug release	Glioma	Brain targeting effect, improved survival of glioma-bearing mice and reduced toxicity	Chai et al. (2017)
	Erythrocyte membrane	Docetaxel nanocrystals	RGD peptide for tumor targeting Cell membrane for long circulation DOX-PLGA for tumor killing	Glioma	Superior tumor accumulation and enhanced therapeutic efficacy	Chai et al. (2019)
	Erythrocyte membrane	miR155-bearing nanogel	Cell membrane prolongs the circulation lifetime M2pep peptide for active targeting miR155 nuclei acid for promotion of cytokine production and shift macrophage and microglia polarization	Glioblastoma	Active tumor-targeting capability, reprograming of microglia and macrophages from M2 to M1 phenotype, excellent tumor inhibition efficacy and prolonged survival	Gao et al. (2021)
	Erythrocyte membrane	Manganous tetroxide nanoparticles	Erythrocyte membrane for high stability, long circulation, and BBB penetration Mn3O4 nanoparticles as antioxidant mimic nanoenzyme T7 peptides for enhancing BBB penetration	Ischemic stroke/MCAO rats	Distinct therapeutic effect for rescuing neurocytes before and after thrombolysis by oxygen sponge effect and scavenging free radicals	Shi et al. (2020)
Platelet	Platelet membrane	ZL006e-loaded dextran derivative polymeric nanoparticle	Recombinant tissue plasminogen activator for thrombin-triggering Tat peptide for BBB penetration Platelet membrane for long circulating and thrombus targeting ZL006e for neuroprotection	Ischemic stroke/MCAO rats	Enhanced anti-ischemic stroke efficacy by recovering the cerebral blood supply and protecting neurons of ischemic penumbra	Xu et al. (2019)
	Platelet nanobubbles	None	Platelet nanobubbles for accurate lesion-targeting and microvascular bio-remodeling of the stroke lesion	Photothrombotic stroke mice	Stroke lesion microvasculature theranostics and reflecting the dynamic structural nature of the recanalization process	Li et al. (2018)
	Platelet membrane	l-Arginine and γ-Fe2O3 magnetic nanoparticles	Platelet membranes for long-term stability and targeting to the damaged blood vessel γ-Fe2O3 nanoparticles for magnetic targeting l-arginine for producing NO	Focal cerebral ischemia mice model	Rapid targeting to ischemic stroke lesions under the guidance of an external magnetic field In situ generation of NO for enhanced vasodilation, recovery of blood flow, and reperfusion of the stroke microvascular	Li et al. (2020b)
Leukocytes	Monocyte	DOX-loaded nanodiamonds	Monocytes for BBB penetration and GBM infiltration	Glioblastoma	Improved tumor drug delivery efficacy and damage-associated molecular patterns emission	Wang et al. (2018)
	Monocytes	Cyclic RGD-modified liposomes loaded with trefoil factor 3	Leukocytes for BBB crossing cRGD for brain targeting	Depression/olfactory bulbectomy rats	Excellent dual-brain-targeting and enhanced antidepressant effects of trefoil factor 3	Qin et al. (2015)
	Macrophages	Gold-silica nanoshells	Macrophage for BBB crossing	Brain metastases of breast cancer	Active targeting to brain metastases	Choi et al. (2012)
	Macrophages	DOX-loaded PLGA nanoparticles	Macrophage for BBB crossing DOX-loaded nanoparticles for tumor therapy	Glioma	Higher brain tumor distribution of nanoparticles and enhanced anti-glioma effect with prolonged survival	Pang et al. (2018)
	Macrophages	Nanocapsule consists of a Dox–silica complex	Macrophage for chemotactic migration Nanocapsule for controlled Dox release and cancer cell killing	Glioma	Efficient tumor growth suppression and minimal systematic toxicity	Zhang et al. (2018)
	Macrophage-derived exosomes	SPIONs and curcumin	Exosomes for BBB crossing Neuropilin-1-targeted peptide for glioma targeting SPION-mediated magnetic flow hyperthermia Curcumin for potent synergistic antitumor therapy	Glioma	Remarkable synergistic anti-glioma effect between MFH and Cur and extended survival of tumor-bearing mice	Jia et al. (2018)
	Macrophage-derived exosomes	Edaravone	Exosomes for brain targeting and improving bioavailability of drug Edaravone for neuroprotection	Ischemic stroke/permanent MCAO rats	Improved pharmacokinetic parameters and enhanced the bioavailability of edaravone Efficient delivery into the ischemic brain and enhanced neuroprotective effect	Li et al. (2020a)
	Macrophage	Polymer backpacks of catalase	Macrophage for BBB crossing Catalase for attenuating free radicals production	LPS-induced encephalitis mice model	Recruitment of macrophages with the attached backpacks to the inflamed brain Attenuated oxidative stress from activated microglia	Klyachko et al. (2017)
	Macrophage-derived exosomes	BDNF	Exosomes for BBB crossing BDNF for depression treatment	LPS-induced encephalitis mice model	Increased concentration of BDNF in inflamed brain	Yuan et al. (2017)
	Macrophage-derived exosomes	Catalase	Exosomes for BBB crossing and preserving drug during circulation Catalase for neuroprotection	6-OHDA mice PD model	Enhanced neuroprotective effects against neurodegeneration	Haney et al. (2015)
	Macrophage-derived exosomes	Curcumin	Exosomes for BBB crossing Curcumin to prevent neuronal death	OA-induced AD murine models	Inhibited Tau phosphorylation, enhanced neuroprotection in AD mice and reversed cognitive dysfunction	Wang et al. (2019)
	Neutrophil	PTX-loaded liposomes	Neutrophil for BBB penetration PTX-loaded liposomes for killing residual tumor cells and inhibiting tumor recurrence	Postoperative glioblastoma by open-window technique	Enhanced BBB penetration, slowed recurrent growth of tumor and improved survival rates	Xue et al. (2017)
	Neutrophil-derived exosomes	DOX	Neutrophils for inflammatory chemotaxis and BBB-crossing	Glioma	Efficient suppress of tumor growth and prolong survival	Wang et al. (2021)
	Neutrophils	Cross-linked DGL nanoparticles containing cis-aconitic anhydride-modified catalase	Neutrophil-mediated inflammatory migration for BBB penetration and ischemic brain targeting Catalase for ischemic stroke treatment	Ischemic stroke/MCAO mice	Reduced the infarct volume and inhibited of ROS-mediated apoptosis	Zhang et al. (2017)
	Neutrophils and monocytes	cRGD liposomes loaded with edaravone	Neutrophils and monocytes for brain targeting Edaravone for ischemia treatment	Ischemic stroke/MCAO mice	Enhanced protection against ischemic injury	Hou et al. (2019)
	Neutrophil membrane-derived nanovesicles	Resolvin D2	Neutrophil membrane-derived nanovesicles for inflamed brain targeting Resolvin D2 mitigate neuroinflammation	Ischemic stroke/ischemia and reperfusion mice	Prevent neurological damage during reperfusion for ischemic stroke therapy	Dong et al. (2019)
	Neutrophil membrane	Mesoporous Prussian blue nanozyme	Neutrophil membrane camouflage for BBB penetration and inflamed brain targeting Nanozyme induce microglia M2 polarization and neuron protection	Ischemic stroke/transient MCAO mice	Relieved ischemic damage and improved neurological function	Feng et al. (2021)

6-OHDA: 6-hydroxydopamine; AD: Alzheimer’s disease; BBB: blood–brain barrier; BDNF: brain-derived neurotrophic factor; DGL: dendrigraft poly-l-lysine; DOX: doxorubicin; LPS: lipopolysaccharide; MCAO: middle cerebral artery occlusion; OA: okadaic acid; PD: Parkinson’s disease; PLGA: poly(lactic-co-glycolic acid); PTX: paclitaxel; RGD: Arg-Gly-Asp-d-Tyr-Lys; SPIONs: superparamagnetic iron oxide nanoparticles.

Catanese L, Tarsia J, Fisher M. (2017). Acute ischemic stroke therapy overview. Circ Res 120:541–58.

 PubMed Web of Science ®Google Scholar

Chai Z, Hu X, Wei X, et al. (2017). A facile approach to functionalizing cell membrane-coated nanoparticles with neurotoxin-derived peptide for brain-targeted drug delivery. J Control Release 264:102–11.

 PubMed Web of Science ®Google Scholar

Gao X, Li S, Ding F, et al. (2021). A virus-mimicking nucleic acid nanogel reprograms microglia and macrophages for glioblastoma therapy. Adv Mater 33:e2006116.

 PubMed Web of Science ®Google Scholar

Shi Q, Montgomery RR. (2010). Platelets as delivery systems for disease treatments. Adv Drug Deliv Rev 62:1196–203.

 PubMed Web of Science ®Google Scholar

Xu J, Wang X, Yin H, et al. (2019). Sequentially site-specific delivery of thrombolytics and neuroprotectant for enhanced treatment of ischemic stroke. ACS Nano 13:8577–88.

 PubMed Web of Science ®Google Scholar

Li M, Liu Y, Chen J, et al. (2018). Platelet bio-nanobubbles as microvascular recanalization nanoformulation for acute ischemic stroke lesion theranostics. Theranostics 8:4870–83.

 PubMed Web of Science ®Google Scholar

Li M, Li J, Chen J, et al. (2020b). Platelet membrane biomimetic magnetic nanocarriers for targeted delivery and in situ generation of nitric oxide in early ischemic stroke. ACS Nano 14:2024–35.

 PubMed Web of Science ®Google Scholar

Wang Q, Cheng H, Peng H, et al. (2015). Non-genetic engineering of cells for drug delivery and cell-based therapy. Adv Drug Deliv Rev 91:125–40.

 PubMed Web of Science ®Google Scholar

Piper K, Depledge L, Karsy M, Cobbs C. (2021). Glioma stem cells as immunotherapeutic targets: advancements and challenges. Front Oncol 11:615704.

 PubMed Web of Science ®Google Scholar

Chinen AB, Guan CM, Ko CH, Mirkin CA. (2017). The impact of protein corona formation on the macrophage cellular uptake and biodistribution of spherical nucleic acids. Small 13:1603847.

 Web of Science ®Google Scholar

Ostrom QT, Gittleman H, Xu J, et al. (2016). CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro Oncol 18:v1–v75.

 PubMed Web of Science ®Google Scholar

Zhang W, Wang M, Tang W, et al. (2018). Nanoparticle-laden macrophages for tumor-tropic drug delivery. Adv Mater 30:e1805557.

 PubMed Web of Science ®Google Scholar

Induruwa I, Moroi M, Bonna A, et al. (2018). Platelet collagen receptor glycoprotein VI-dimer recognizes fibrinogen and fibrin through their D-domains, contributing to platelet adhesion and activation during thrombus formation. J Thromb Haemost 16:389–404.

 PubMed Web of Science ®Google Scholar

Lapchak PA. (2010). A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother 11:1753–63.

 PubMed Web of Science ®Google Scholar

Khandelwal P, Yavagal DR, Sacco RL. (2016). Acute ischemic stroke intervention. J Am Coll Cardiol 67:2631–44.

 PubMed Web of Science ®Google Scholar

Yuan D, Zhao Y, Banks WA, et al. (2017). Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials 142:1–12.

 PubMed Web of Science ®Google Scholar

Hamidi M, Tajerzadeh H. (2003). Carrier erythrocytes: an overview. Drug Deliv 10:9–20.

 PubMed Web of Science ®Google Scholar

Wang C, Li K, Li T, et al. (2018). Monocyte-mediated chemotherapy drug delivery in glioblastoma. Nanomedicine (Lond) 13:157–78.

 PubMed Web of Science ®Google Scholar

Xue J, Zhao Z, Zhang L, et al. (2017). Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat Nanotechnol 12:692–700.

 PubMed Web of Science ®Google Scholar

Wang H, Sui H, Zheng Y, et al. (2019). Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the Tau protein through the AKT/GSK-3β pathway. Nanoscale 11:7481–96.

 PubMed Web of Science ®Google Scholar

Zhang C, Ling CL, Pang L, et al. (2017). Direct macromolecular drug delivery to cerebral ischemia area using neutrophil-mediated nanoparticles. Theranostics 7:3260–75.

 PubMed Web of Science ®Google Scholar

Haumann R, Videira JC, Kaspers GJL, et al. (2020). Overview of current drug delivery methods across the blood–brain barrier for the treatment of primary brain tumors. CNS Drugs 34:1121–31.

 PubMed Web of Science ®Google Scholar

De Lange ECM, Van Den Brink W, Yamamoto Y, et al. (2017). Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics. Expert Opin Drug Discov 12:1207–18.

 PubMed Web of Science ®Google Scholar

Fang RH, Kroll AV, Gao W, Zhang L. (2018). Cell membrane coating nanotechnology. Adv Mater 30:e1706759.

 PubMed Web of Science ®Google Scholar