Biology subjects

Arguiri, E.

Publications and source records attributed to Arguiri, E..

4 recordsLinked to original sources

bioRxiv2024

A percolation-type criticality threshold controls immune protein coating of surfaces

When a material enters the body, it is immediately attacked by hundreds of proteins, organized into complex networks of binding interactions and reactions. How do such complex systems interact with a material, "deciding" whether to attack? We focus on the "complement" system of [~]40 blood proteins that bind microbes, nanoparticles, and medical devices, initiating inflammation. We show a sharp threshold for complement activation upon varying a fundamental material parameter, the surface density of potential complement attachment points. This sharp threshold manifests at scales spanning single nanoparticles to macroscale pathologies, shown here for diverse engineered and living materials. Computational models show these behaviors arise from a minimal subnetwork of complement, manifesting percolation-type critical transitions in the complement response. This criticality switch explains the "decision" of a complex signaling network to interact with a material, and elucidates the evolution and engineering of materials interacting with the body.

biophysics↗

bioRxiv2024

Marginated neutrophils in the lungs effectively compete for nanoparticles targeted to the endothelium, serving as a part of the reticuloendothelial system

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has not achieved this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/597904v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@17e0518org.highwire.dtl.DTLVardef@809eb6org.highwire.dtl.DTLVardef@33d9a7org.highwire.dtl.DTLVardef@169863_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

A combination of physicochemical tropism and affinity moiety targeting of lipid nanoparticles enhances organ targeting

Two camps have emerged in the targeting of nanoparticles to specific organs and cell types: affinity moiety targeting, which conjugates nanoparticles to antibodies or similar molecules that bind to known surface markers on cells; and physicochemical tropism, which achieves specific organ uptake based on the nanoparticles physical or chemical features (e.g., binding to endogenous proteins). Because these camps are largely non-overlapping, the two targeting approaches have not been directly compared or combined. Here we do both, using intravenous (IV) lipid nanoparticles (LNPs) whose original design goal was targeting to the lungs endothelial cells. For an affinity moiety, we utilized PECAM antibodies, and for physicochemical tropism, we used cationic lipids, both having been heavily studied for lung targeting. Surprisingly, the two methods yield nearly identical levels of lung uptake. However, aPECAM LNPs display much greater specificity for endothelial cells. Intriguingly, LNPs that possess both targeting methods had >2-fold higher lung uptake than either method alone. The combined-targeting LNPs also achieved greater uptake in already inflamed lungs, and greater uptake in alveolar epithelial cells. To understand how the macro-scale route of delivery affects organ targeting, we compared IV injection vs. intra-arterial (IA) injection into the carotid artery. We found that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the brain, a level superior to any other reported targeting method. Thus, combining affinity moiety targeting and physicochemical tropism provides benefits that neither targeting method achieves alone. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/568061v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@281d31org.highwire.dtl.DTLVardef@1948026org.highwire.dtl.DTLVardef@693f99org.highwire.dtl.DTLVardef@1ce74cb_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke

After more than 100 failed drug trials for acute ischemic stroke (AIS), one of the most commonly cited reasons for the failure has been that drugs achieve very low concentrations in the at-risk penumbra. To address this problem, here we employ nanotechnology to significantly enhance drug concentration in the penumbras blood-brain barrier (BBB), whose increased permeability in AIS has long been hypothesized to kill neurons by exposing them to toxic plasma proteins. To devise drug-loaded nanocarriers targeted to the BBB, we conjugated them with antibodies that bind to various cell adhesion molecules on the BBB endothelium. In the transient middle cerebral artery occlusion (tMCAO) mouse model, nanocarriers targeted with VCAM antibodies achieved the highest level of brain delivery, nearly 2 orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles loaded with either a small molecule drug (dexamethasone) or mRNA (encoding IL-10) reduced cerebral infarct volume by 35% or 73%, respectively, and both significantly lowered mortality rates. In contrast, the drugs delivered without the nanocarriers had no effect on AIS outcomes. Thus, VCAM-targeted lipid nanoparticles represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/544645v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@86762dorg.highwire.dtl.DTLVardef@1b89a2aorg.highwire.dtl.DTLVardef@916d85org.highwire.dtl.DTLVardef@1ad4670_HPS_FORMAT_FIGEXP M_FIG C_FIG Acute ischemic stroke induces upregulation of VCAM. We specifically targeted upregulated VCAM in the injured region of the brain with drug- or mRNA-loaded targeted nanocarriers. Nanocarriers targeted with VCAM antibodies achieved the highest brain delivery, nearly orders of magnitude higher than untargeted ones. VCAM-targeted nanocarriers loaded with dexamethasone and mRNA encoding IL-10 reduced infarct volume by 35% and 73%, respectively, and improved survival rates.

pharmacology and toxicology↗