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

Abstract

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 penumbra 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.

Precision treatment of viral pneumonia through macrophage-targeted lipid nanoparticle delivery

“…However, they are also challenging targets for transfection ( 41 ). To achieve effective targeted delivery to macrophages, we employed an antibody conjugation strategy as previously described ( 42 ) In short, a strain-promoted alkyne azide cycloaddition (SPAAC) click chemistry method was utilized to integrate DBCO-activated F4/80 (a classical macrophage-specific marker in mice) antibody with as-prepared azide-4-O10b1-LNP (F4/80 LNP or MacLNP, Fig. 3 A ), with IgG2a-conjugated LNP (IgG LNP or Control LNP) as negative controls.…”

Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage

“… 19 More recently, it has been reported that targeting CAMs, especially VCAM, with mAbs and nanocarriers represent a promising direction for innovative stroke therapies. 20 …”

“…Another limitation of our approach is represented by the lack of specificity for the ischemic region, as it occurs with DDSs equipped with antibodies against penumbra-related selective targets. 20 …”

Interview with Drew Weissman, 2023 Nobel Laureate in Physiology or Medicine

“…[ 1 ] We can target the brain with anti-VCAM antibodies. [ 2 , 3 , 4 ] We can target T cells with a variety of markers. [ 5 , 6 , 7 ] We published last year that we could make CAR-T cells in vivo and cure a disease in a mouse.…”