Nanoparticles for Thrombolytic Therapy in Ischemic Stroke: A Systematic Review and Meta-Analysis of Preclinical Studies.

Recombinant tissue plasminogen activator (rtPA) remains the standard thrombolytic treatment for ischemic stroke. Different types of nanoparticles have emerged as promising tools to improve the benefits and decrease the drawbacks of this therapy. Among them, cell membrane-derived (CMD) nanomedicines have gained special interest due to their capability to increase the half-life of particles in blood, biocompatibility, and thrombus targeting.

Fabrication of nanoparticles with precisely controllable plasmonic properties as tools for biomedical applications.

Metal nanoparticles are established tools for biomedical applications due to their unique optical properties, primarily attributed to localized surface plasmon resonances. They show distinct optical characteristics, such as high extinction cross-sections and resonances at specific wavelengths, which are tunable across the wavelength spectrum by modifying the nanoparticle geometry. These attributes make metal nanoparticles highly valuable for sensing and imaging in biology and medicine.

Engineered cell membrane-cloaked metal-organic framework nanocrystals for intracellular cargo delivery.

This investigation demonstrates the development and functionality of cell membrane-cloaked UiO-67 nanosized metal-organic frameworks (NMOFs), which are engineered for precise intracellular delivery of encapsulated cargoes. Utilizing the robust and porous nature of UiO-67, we enveloped these NMOFs with fusogenic cell membrane-derived nanovesicles (FCSMs) sourced from adenocarcinomic human alveolar basal epithelial (A549) cells. This biomimetic coating enhances biocompatibility and leverages the homotypic targeting capabilities of the cell-derived coatings, facilitating direct cytoplasmic delivery and avoiding endolysosomal entrapment.

Preclinical validation of human recombinant glutamate-oxaloacetate transaminase for the treatment of acute ischemic stroke.

The blood enzyme glutamate-oxaloacetate transaminase (GOT) has been postulated as an effective therapeutic to protect the brain during stroke. To demonstrate its potential clinical utility, a new human recombinant form of GOT (rGOT) was produced for medical use. We tested the pharmacokinetics and evaluated the protective efficacy of rGOT in rodent and non-human primate models that reflected clinical stroke conditions.

Modulation of Abundance and Location of High-Mobility Group Box 1 in Human Microglia and Macrophages under Oxygen-Glucose Deprivation.

While stroke represents one of the main causes of death worldwide, available effective drug treatment options remain limited to classic thrombolysis with recombinant tissue plasminogen activator (rtPA) for arterial-clot occlusion. Following stroke, multiple pathways become engaged in producing a vicious proinflammatory cycle through the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and heat shock protein 70 kDa (HSP72). HMGB1, in particular, can activate proinflammatory cytokine production when acetylated (AcHMGB1), a form that prefers cytosolic localization and extracellular release.

Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke.

Background: Intravenous administration of fibrinolytic drugs, such as recombinant tissue plasminogen activator (rtPA) is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and risk of hemorrhagic transformations. Platelet membrane-based nanocarriers have received increasing attention for ischemic stroke therapies, as they have natural thrombus-targeting activity, can prolong half-life of the fibrinolytic therapy, and reduce side effects.

Fusogenic Cell-Derived nanocarriers for cytosolic delivery of cargo inside living cells.

A surface-engineered cell-derived nanocarrier was developed for efficient cytosolic delivery of encapsulated biologically active molecules inside living cells. Thus, a combination of aromatic-labeled and cationic lipids, instrumental in providing fusogenic properties, was intercalated into the biomimetic shell of self-assembled nanocarriers formed from cell membrane extracts. The nanocarriers were loaded, as a proof of concept, with either bisbenzimide molecules, a fluorescently labeled dextran polymer, the bicyclic heptapeptide phalloidin, fluorescently labeled polystyrene nanoparticles or a ribonucleoprotein complex (Cas9/sgRNA).

Nanoparticle-based immunotherapeutics: From the properties of nanocores to the differential effects of administration routes.

The engagement with the immune system is one of the main cornerstones in the development of nanotechnologies for therapy and diagnostics. Recent advances have made possible the tuning of features like size, shape and biomolecular modifications that influence such interactions, however, the capabilities for immune modulation of nanoparticles are still not well defined and exploited. This review focuses on recent advances made in preclinical research for the application of nanoparticles to modulate immune responses, and the main features making them relevant for such applications.

Nanosized metal-organic frameworks as unique platforms for bioapplications.

Metal-organic frameworks (MOFs) are extremely versatile materials, which serve to create platforms with exceptional porosity and specific reactivities. The production of MOFs at the nanoscale (NMOFs) offers the possibility of creating innovative materials for bioapplications as long as they maintain the properties of their larger counterparts. Due to their inherent chemical versatility, synthetic methods to produce them at the nanoscale can be combined with inorganic nanoparticles (NPs) to create nanocomposites (NCs) with one-of-a-kind features.

Biomimetic cell-derived nanocarriers in cancer research.

Nanoparticles have now long demonstrated capabilities that make them attractive to use in biology and medicine. Some of them, such as lipid nanoparticles (SARS-CoV-2 vaccines) or metallic nanoparticles (contrast agents) are already approved for their use in the clinic. However, considering the constantly growing body of different formulations and the huge research around nanomaterials the number of candidates reaching clinical trials or being commercialized is minimal.

High-yield halide-assisted synthesis of metal-organic framework UiO-based nanocarriers.

The synthesis of nanosized metal-organic frameworks (NMOFs) is requisite for their application as injectable drug delivery systems (DDSs) and other biorelevant purposes. Herein, we have critically examined the role of different synthetic parameters leading to the production of UiO-66 crystals smaller than 100 nm. Of note, we demonstrate the co-modulator role conferred by halide ions, not only to produce NMOFs with precise morphology and size, but also to significantly improve the reaction yield.

Sonosensitive capsules for brain thrombolysis increase ischemic damage in a stroke model.

Background: Ischemic stroke is the most common cerebrovascular disease and is caused by interruption of blood supply to the brain. To date, recombinant tissue plasminogen activator (rtPA) has been the main pharmacological treatment in the acute phase. However, this treatment has some drawbacks, such as a short half-life, low reperfusion rate, risk of hemorrhagic transformations, and neurotoxic effects.

Plasmonic-Assisted Thermocyclizations in Living Cells Using Metal-Organic Framework Based Nanoreactors.

We describe a microporous plasmonic nanoreactor to carry out designed near-infrared (NIR)-driven photothermal cyclizations inside living cells. As a proof of concept, we chose an intramolecular cyclization that is based on the nucleophilic attack of a pyridine onto an electrophilic carbon, a process that requires high activation energies and is typically achieved in bulk solution by heating at ∼90 °C. The core-shell nanoreactor (NR) has been designed to include a gold nanostar core, which is embedded within a metal-organic framework (MOF) based on a polymer-stabilized zeolitic imidazole framework-8 (ZIF-8).

New Approaches in Nanomedicine for Ischemic Stroke.

Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in developed countries. Therapeutic methods such as recanalization approaches, neuroprotective drugs, or recovery strategies have been widely developed to improve the patient's outcome; however, important limitations such as a narrow therapeutic window, the ability to reach brain targets, or drug side effects constitute some of the main aspects that limit the clinical applicability of the current treatments. Nanotechnology has emerged as a promising tool to overcome many of these drug limitations and improve the efficacy of treatments for neurological diseases such as stroke.

808 nm-activable core@multishell upconverting nanoparticles with enhanced stability for efficient photodynamic therapy.

Background: The unique upconversion properties of rare-earth-doped nanoparticles offers exciting opportunities for biomedical applications, in which near-IR remote activation of biological processes is desired, including in vivo bioimaging, optogenetics, and light-based therapies. Tuning of upconversion in purposely designed core-shell nanoparticles gives access to biological windows in biological tissue. In recent years there have been several reports on NIR-excitable upconverting nanoparticles capable of working in biological mixtures and cellular settings.

Plasmonic Cell-Derived Nanocomposites for Light-Controlled Cargo Release inside Living Cells.

Translating the potential of thermoplasmonics to cell-derived nanomaterials offers exciting opportunities to fabricate beyond state-of-art artificial biomimetic nanocomposites that upon illumination perform active tasks such as delivery of cargo in complex, dynamic media such as the cytosol of cells. Cell-derived nanoparticles have shown stunning potential to implement cell-specific functions, such as long blood circulation or targeting capabilities, into advanced drug delivery nanosystems. The biomimicry nanotechnology has now advanced to offer new and exciting opportunities to improve the commonly poor in vivo performance of most current nanomedicines, including evading the immune system and targeting specific tissues such as tumors, the latest remaining among the most wanted breakthroughs in nanomedicine.

In vivo ultrasound-activated delivery of recombinant tissue plasminogen activator from the cavity of sub-micrometric capsules.

External stimuli such as light, magnetic fields or ultrasounds allow for controlled drug release from nanocarriers with spatiotemporal resolution. Such tetherless approaches may become a straightforward solution to overcome the specificity problems typically associated with nanomedicines. Most of current nanomedicines suffer of very low specificity in vivo, thus rendering efficient targeted delivery among the most wanted breakthroughs in the fields of nanotechnology and medicine.

Aqueous Stable Gold Nanostar/ZIF-8 Nanocomposites for Light-Triggered Release of Active Cargo Inside Living Cells.

A plasmonic core-shell gold nanostar/zeolitic-imidazolate-framework-8 (ZIF-8) nanocomposite was developed for the thermoplasmonic-driven release of encapsulated active molecules inside living cells. The nanocomposites were loaded, as a proof of concept, with bisbenzimide molecules as functional cargo and wrapped with an amphiphilic polymer that prevents ZIF-8 degradation and bisbenzimide leaking in aqueous media or inside living cells. The demonstrated molecule-release mechanism relies on the use of near-IR light coupled to the plasmonic absorption of the core gold nanostars, which creates local temperature gradients and thus, bisbenzimide thermodiffusion.

Aqueous Synthesis of Copper(II)-Imidazolate Nanoparticles.

A green, simple, and efficient room-temperature aqueous synthetic route for the fabrication of novel porous coordination polymer nanoparticles (NPs) composed of Cu and imidazolate was developed. Colloidal stability, morphology changes, and structural and chemical integrity of the developed NPs, in several solvents having different polarity, were investigated. Basic physicochemical properties of selected NPs (i.

Human DMBT1-Derived Cell-Penetrating Peptides for Intracellular siRNA Delivery.

Small interfering RNA (siRNA) is a promising molecule for gene therapy, but its therapeutic administration remains problematic. Among the recently proposed vectors, cell-penetrating peptides show great promise in in vivo trials for siRNA delivery. Human protein DMBT1 (deleted in malignant brain tumor 1) is a pattern recognition molecule that interacts with polyanions and recognizes and aggregates bacteria.

Locating Reactive Groups on Nanomaterials with Gold Nanoclusters: Toward a Surface Reactive Site Map.

Nanoparticles (NPs) are often functionalized with reactive groups such as amines and thiols for the subsequent conjugation of further molecules, e.g., stabilizing polymers, drugs, and proteins for targeting cells or specific diseases.

Regimes of Biomolecular Ultrasmall Nanoparticle Interactions.

Ultrasmall nanoparticles (USNPs), usually defined as NPs with core in the size range 1-3 nm, are a class of nanomaterials which show unique physicochemical properties, often different from larger NPs of the same material. Moreover, there are also indications that USNPs might have distinct properties in their biological interactions. For example, recent in vivo experiments suggest that some USNPs escape the liver, spleen, and kidney, in contrast to larger NPs that are strongly accumulated in the liver.

Advances toward More Efficient Targeted Delivery of Nanoparticles in Vivo: Understanding Interactions between Nanoparticles and Cells.

In this Perspective, we describe current challenges and recent advances in efficient delivery and targeting of nanoparticles in vivo. We discuss cancer therapy, nanoparticle-biomolecule interactions, nanoparticle trafficking in cells, and triggers and responses to nanoparticle-cell interactions. No matter which functionalization strategy to target cancer is chosen, passive or active targeting, more than 99% of the nanoparticles administered in vivo end up in the mononuclear phagocytic system, mainly sequestered by macrophages.

Identification of Receptor Binding to the Biomolecular Corona of Nanoparticles.

Biomolecules adsorbed on nanoparticles are known to confer a biological identity to nanoparticles, mediating the interactions with cells and biological barriers. However, how these molecules are presented on the particle surface in biological milieu remains unclear. The central aim of this study is to identify key protein recognition motifs and link them to specific cell-receptor interactions.

Mapping of Molecular Structure of the Nanoscale Surface in Bionanoparticles.

Characterizing the orientation of covalently conjugated proteins on nanoparticles, produced for in vitro and in vivo targeting, though an important feature of such a system, has proved challenging. Although extensive physicochemical characterization of targeting nanoparticles can be addressed in detail, relevant biological characterization of the nanointerface is crucial in order to select suitable nanomaterials for further in vitro or in vivo experiments. In this work, we adopt a methodology using antibody fragments (Fab) conjugated to gold nanoparticles (immunogold) to map the available epitopes on a transferrin grafted silica particle (SiO-PEG-Tf) as a proxy methodology to predict nanoparticle biological function, and therefore cellular receptor engagement.