Targeted pathophysiological treatment of ischemic stroke using nanoparticle-based drug delivery system

Abstract

Ischemic stroke poses significant challenges in terms of mortality and disability rates globally. A key obstacle to the successful treatment of ischemic stroke lies in the limited efficacy of administering therapeutic agents. Leveraging the unique properties of nanoparticles for brain targeting and crossing the blood-brain barrier, researchers have engineered diverse nanoparticle-based drug delivery systems to improve the therapeutic outcomes of ischemic stroke. This review provides a concise overview of the pathophysiological mechanisms implicated in ischemic stroke, encompassing oxidative stress, glutamate excitotoxicity, neuroinflammation, and cell death, to elucidate potential targets for nanoparticle-based drug delivery systems. Furthermore, the review outlines the classification of nanoparticle-based drug delivery systems according to these distinct physiological processes. This categorization aids in identifying the attributes and commonalities of nanoparticles that target specific pathophysiological pathways in ischemic stroke, thereby facilitating the advancement of nanomedicine development. The review discusses the potential benefits and existing challenges associated with employing nanoparticles in the treatment of ischemic stroke, offering new perspectives on designing efficacious nanoparticles to enhance ischemic stroke treatment outcomes.

Keywords: Drug delivery; Ischemic stroke; Nanoparticle; Pathophysiology; Target therapy.

Fig. 1

A Annual number of publications worldwide from January 1, 2003 to February 29, 2024. B The keyword co-occurrence analysis provides the top 10 keywords with co-occurrence frequency rankings. C Keyword co-occurrence analysis provides a centrality ranking of keywords. D Visualization of keyword co-occurrence analysis (The size of each node indicates the frequency of the word's occurrence in outputs, with larger circles representing higher frequencies. The thickness of the pink outer ring around each node signifies its centrality. The thickness of the connecting lines reflects the proximity of the relationship between two words)

Fig. 2

A Schematic representation of the principle of intravenous thrombolysis for the treatment of AIS. B Schematic diagram of mechanical thrombectomy for IS. C A schematic diagram of the combined treatment (bridging therapy) of intravenous thrombolysis and mechanical thrombectomy for IS

Fig. 3

Schematic diagram of the pathophysiological mechanisms involved in IS

Fig. 4

Oxidative stress and mitochondrial dysfunctions in IS

Fig. 5

Bioinspired nanosponge for salvaging IS via free radical scavenging and self-adapted oxygen regulating. A Schematic diagram of MNET salvaging in an acute IS via combining free radical scavenging and natural oxygen sponge effect. B Blood stability and BBB-crossing ability of MNET. C Protective effect of MNET via ROS scavenging and hypoxia relief in vitro. D The therapeutic effect of MNET in vivo for rescuing IS before thrombolysis. E The therapeutic effect of MNET in vivo for rescuing IS after thrombolysis. Copyright © 2020, American Chemical Society

Fig. 6

Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for IS treatment. A Schematic illustration of targeted treatment of IS by ROS-responsive NPs loaded with PU and decorated with SS31. B Neuroprotection on SH-SY5Y cells simulated oxidative stress environment after acute IS. C Characterization of thermo-sensitive gels containing different therapeutic agents and ex vivo biodistribution of therapeutic NPs. D In vivo anti-IS efficacy. © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V

Fig. 7

The cascade of glutamate excitotoxicity in IS

Fig. 8

Bioengineered boronic ester-modified dextran polymer NPs as ROS responsive nanocarrier for IS treatment. A Schematic design of the SHp-RBC-NP/NR2B9C. B In vitro cell-based studies. C In vivo pharmacokinetics and fluorescent image of rhodamine-labeled free NR2B9C, NP, RBC-NP, and SHp-RBC-NP in the ischemic brain sections. D The neuroscore and infarct size were evaluated 24 h after the I/R and in vivo safety evaluation. Copyright © 2018, American Chemical Society

Fig. 9

The BBB breakdown and neuroinflammation in IS. © By Figdraw

Fig. 10

C-176-loaded Ce⁴⁺ DNase NPs synergistically inhibit the cGAS-STING pathway for IS treatment. A The therapeutic mechanism of NTA/Ce⁴⁺/C-176 NPs. B NTA/Ce⁴⁺/C-176 decreased neuroinflammation and increased neurogenesis in vivo. C Effect of NTA/Ce⁴⁺/C-176 on brain infarct volume and functional motor recovery after stroke. © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd

Fig. 11

A triple-targeted rutin-based self-assembled delivery vector for treating IS by vascular normalization and anti-inflammation via ACE2/Ang1‑7 signaling. A SHR micelles promoted microglial transformation. B SHR anti-inflammation effect. © 2023 The Authors. Published by American Chemical Society

Fig. 12

Cell death process involved in IS. © By Figdraw

Fig. 13

Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries. A Schematic illustration of DA7R-SDF-1-EV nano-missile (Dual-EV) treatment on IS. B Effect of M2-EV on NSC differentiation. C Internalization of different EVs by HUVECs and its recruitment effect on NSCs. D Ischemic brain-targeting ability of Dual-EV in vivo. © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V

Fig. 14

A DNA nanostructure-based neuroprotectant against neuronal apoptosis via inhibiting toll-like receptor 2 signaling pathway in acute IS. A Schematic diagram of tFNAs as neuroprotective agents for the treatment of IS. B Protection of tFNAs for apoptosis of SH-SY5Y cells via interfering with the ischemia cascades in OGD/R models in vitro. C tFNAs reduce the infarct volume, alleviate mortality, and ameliorate functional outcomes of tMCAO models. D Potential mechanism of the protective effects of tFNAs on IS. © 2021 American Chemical Society

Fig. 15

Nanomedicine directs neuronal differentiation of neural stem cells via silencing long noncoding RNA for stroke therapy. A Schematic illustration of the preparation for MRI-Visible siRNA/ASO complexed nanomedicine, directed neuronal differentiation of transplanted NSCs by silencing pnky lncRNA and MRI tracking of NSCs in a mouse stroke model. B In vitro and in vivo neuronal differentiation mediated by Pnky downregulation. C Safety and efficiency of Pnky knockdown with MRI-visible nanomedicine. © 2021 American Chemical Society

Fig. 16

Targeted treatment of IS by bioactive NP-derived ROS-responsive and inflammation-resolving NPs. A TPCD NP inhibited microglial activation. B TPCD NP attenuated oxidative and inflammatory responses in MCAO mice. Copyright © 2021, American Chemical Society

Fig. 17

Neutrophil-bomimetic “nanobuffer” for remodeling the microenvironment in the infarct core and protecting neurons in the penumbra via neutralization of detrimental factors to treat IS. A Schematic illustration of LA-NM-NP/CBD preparation and its nanobuffer effect. B Nanobuffer effect of LA-NM-NP/CBDs against the core and neuroprotective effect for the penumbra in vitro. C Nanobuffer formed at the infarct core by the accumulation of LA-NM-NPs and buffering detrimental erosions in vivo. Copyright © 2022, American Chemical Society