Table 1.
Nanoparticles for stroke treatment depending on the hemodynamic stroke phase.
| Phase | Target | NPs | Payload | Outcome | Model | Ref. |
|---|---|---|---|---|---|---|
| HYPERACUTE | Rho-kinase | Liposomes | Fausidil | Protection against tPA harmful effects | SD MCAO rat | [62] |
| ROS | Polymeric | Resveratrol | Protection against EVT harmful effects | SD tMCAO rat | [58] | |
| Biodegradable PLGA | CAT and SOD | Protection against tPA harmful effects | SD thrombo rat | [63] | ||
| Fibrin | PEG-PCL | rtPA | Improved and no harmful reperfusion | SD MCAO rat | [64] | |
| GPIIb/IIIa of platelets | Liposomes with FGG C-terminal peptide | tPA | Improved reperfusion with no harmful effect | SD IVC trhombosis rat | [65] | |
| P-selectin of platelets | Polysaccharide-poly-IBCA + Fucoidan | rtPA | Improved reperfusion without harmful effect | Rat venous thrombosis | [66] | |
| TfR/GLUT receptor | Liposome dual-target nanocarrier | ZL006 | Efficient trhombolysis and reduced cell apoptosis and ischemia | SD MCAO rat/ ICR mice | [67] | |
| MMP-9 | Quantum dot nanoplexes | MMP-9 siRNA | ECM proteins upregulation and BBBP decrease | Human BMVEC/NHAs | [68] | |
| Amphibilic peptide | MMP-9-inhibiting peptide | MMP-9 inhibition | BBB model: hCMEC/D3 cell line |
[69] | ||
| Ps80-coated PLGA | TIMP-1 | Early inhibition of MMP-9 | In vitro: RBE4 / RBCEC+ astrocytes; In vivo: mice | [70] | ||
| Polymeric NPs | CD147-antagonist peptide-9 | Reduced brain infarct size and HT appearance | C57BL/6 tMCAO mice | [71] | ||
| ACUTE | Microglia activation | Adipose-derived stem cells exosomes | miR-126 | Inhibition of microglial activation and inflammatory factors expression | MCAO rats | [72] |
| Retinoic acid NPs | Retinoic acid | Reduction in microglia activation | N9 microglia cells; Organotypic hippocampal slices culture |
[73] | ||
| Transferrin receptor | PEGylated Selenium NPs | siRNA STAT3 | Suppression of excessive inflammation and oxidative metabolism | MCAO rats | [59] | |
| SUBACUTE | Stroke cavity | RGD-HA hydrogel | VEGF | Better angioenesis/establish axonal nets | Mouse MCAO | [74] |
| PCN-NPs | SDF-1a, bFGF | Enhanced neurogenesis and angiogenesis | PTI | [75] | ||
| Ischemic area | SDF-1-loaded micelles | SDF-1α | Enhanced neurogenesis and angiogenesis | Rat MCAO | [76] | |
| Integrin receptor | cRGD-dendrimer | N/A | Improved angiogenesis | PTI | [54] | |
| DMAPA-NPs | HIF-1α-AA plasmid | Enhanced angiogenesis, reduced infarct volume, and improved neurological function | Zebrafish AIS/Rat MCAO | [77] | ||
| RGD-EVs | miR-210 | Improved angiogenesis | MCAO mouse | [78] | ||
| Neurons | RVG-EVs | miR-124 | Enhanced cortical neurogenesis | PTI | [60] | |
| CHRONIC | siRNA delivery/EPCs | Alkyl-PEI/SPIO | PHD2 siRNA | MRI/BLI tracking, Increased functional recovery, vascularization, neurogenesis, and Cxcr4 expression inducing cell mobilization and migration. Decreased infarct volume | In vitro: umbellical cord UCB EPCs In vivo: BALB/c nude mice |
[79] |
| Angio/neurogenesis | PEI | retinoic acid | NSC proliferation and differentiation, protection of ECs ischemic death | hEPC from stroke patients | [80] | |
| Neurovascular protection | PEI | miR-195 | Improved neurogenesis, neuroprotection EC function/ less inflammation | In vitro: SH-sy5 In vivo: tMCAO/MCAO rat |
[81] | |
| Sequential growth factor release | PLGA and PLGA/ poly(sebacic acid) NPs on HAMC hydrogel | EGF-PEG and erythropoietin | Controlled release of growth factor to the brain circumvents the BBB, neurogenesis | C57BL/6 murine stroke | [82] | |
| EPO dose reduction | PLGA | Erythropoietin | Effects of the EPO-NPs equivalent to 10 times the amount of free EPO | Unilateral AIS neonatal rat | [83] | |
| Increase efficiency of drug delivery | PLGA NPs in HAMC hydrogel | Cyclosporin A | Higher levels of CsA delivered with local injection, NSC survival, proliferation, and migration | Long-Evans endothelin-1 stroke rats | [84] | |
| Neural restoration via angiogenesis | PLGA NPs in a HA scaffold + anti-NOGO receptor antibody | VEGF and Ang-1 | Behavioral improvement, vascularization, axonal growth | In vitro: HUAECs/ primary NSCs; in vivo: C57BL/6J MCAO rats | [85] | |
| Identification of new stroke therapeutics | PLGA | miR-124 | SVZ neurogenesis, increased survival and neuronal differentiation of NSCs in vitro but no effects in vivo | In vitro: primary NSCs/ In vivo: C57BL/6 J PTI mice | [86] | |
| BBB crossing | Chitosan NPs + anti-tfR antibody | bFGF | Accumulation of NPs in brain parenchyma, neuroprotection | MCAO swiss albino mice | [43] | |
| Biomolecules delivery | Enantiomeric protein nanocapsules in HA hydrogel + RGD motif | VEGF and PDGF | Controlled release thanks to MMP-sensitive crosslinker, improved vascularization | C57BL/6 MCAO mice | [87] | |
| Increased brain delivery of VEGF | Liposomes functionalized with transferrin | VEGF | Neurogenesis, increased mRNA and protein VEGF, decreased infarct volume, functional recovery | SD MCAO rats | [88] | |
| Design of stroke dual-targeted lipososmes | liposomes conjugated with T7 peptide and stroke homing peptide (SHp) | neuroprotectant ZL006 | BBB crossing, targeting of the ischemic area, improved neurological deficit, protection against apoptosis | In vitro: BCEC cells and PC-12 cells In vivo: SD MCAO rat and mice |
[89] | |
| Stroke therapy with EVs | EVs from MSCs | N/A | Increased axonal density, functional recovery, neurogenesis, angiogenesis | MCAO Wistar rats | [90] | |
| MSC and MSC-EVs comparison |
EVs from BMSCs | N/A | Improved motor coordination, neurogenesis, neuroprotection, angiogenesis | MCAO Mice C57BL6 |
[91] | |
| EVs’ study as therapeutics | Evs from MSCs | miR-133b | Motor recovery, neurite remodeling | In vitro: Primary neurons In vivo: MCAO rats | [92] | |
| Neurogenesis | EVs from BMSCs modified with transferrin | Enkephalin | Increased neuronal density, decreased p53 and caspase-3 levels | In vitro: primary neurons In vivo: MCAO rats |
[93] | |
| Therapeutic effect of EVs from ADSC | EVs from adipose-derived stem cells (ADSC) | miR-126 | Neurogenesis, angiogenesis, functional recovery | MCAO rats | [72] | |
| Effect of urine EVs on neurogenesis | Evs from urine | miR-26a | Proliferation and differentiation of NSC | MCAO rats | [94] |
N/A = not available; SD = Sprague Dawley; MCAO = middle cerebral artery occlusion; tMCAO = transitient middle cerebral artery occlusion; ROS = reactive oxygen species; BMVE = microvascular endothelial cells; SDF-1α = stroma cell-derived factor 1; NHA = normal human astrocytes: FGG = fibrinogen gamma chain; IBCA = isobutylcyanoacrylate; EVT = endovascular thrombectomy; PLGA = poly(lactic-co-glycolic acid); rtPA = recombinant tissue plasminogen activator; IVC = inferior vena-cava; MMP = matrix metalloproteinase; ECM = extracellular matrix; BBB = blood-brain barrier; NPs = nanoparticles; HT = hemorrhagic transformation; PAA = polyacrylic acid; EV = extracellular veshicles.