Abstract WP340: From Neurovascular Challenge to Therapeutic Opportunity: VCAM-Targeted Nanocarriers in Acute Ischemic Stroke and Intracranial Hemorrhage

Stroke · 2026-01-29

Acute neurovascular diseases such as ischemic stroke (AIS) and intracerebral hemorrhage (ICH) remain leading causes of mortality and disability. Both are fueled by neuroinflammation and blood-brain barrier (BBB) disruption, which challenge effective brain drug delivery and limit current therapeutic impact. We have developed VCAM-targeted nanocarriers (T-NCs) that leverage vascular cell adhesion molecule-1 upregulation at the inflamed BBB, achieving highly selective targeting: 20-fold higher uptake by BBB endothelial cells over untargeted controls and up to 100-fold compared to free drugs, surpassing transferrin receptor-targeted approaches by 15-fold. In AIS models, VCAM T-NCs delivered small molecules (dexamethasone and fingolimod), proteins, and mRNAs (luciferase, Cre-recombinase, IL-10, Mfsd2A, tight junction components, and thrombomodulin) directly to the BBB endothelium in affected regions. This strategy produced marked reductions in brain inflammation, cerebral edema, and infarct volume (by up to 65%), and improved survival rates with mRNA/IL-10 cargo. Critical mechanistic benefits included enhancing BBB homeostasis, suppressing caveolar transcytosis, and reinforcing junctional integrity. Notably, VCAM T-NCs transformed the brain vasculature into a depot for sustained drug release and a “biofactory” for proteins via endothelial transfection—spatial and functional distribution confirmed by mass spectrometry and CLARITY imaging in AIS. Mechanistically, AIS treatment led to an approximately 75% reduction in macrophage infiltration in the injured hemisphere. In ICH, current treatments remain mostly supportive, and effective disease-targeted therapies are lacking. VCAM T-NCs loaded with IL-10 mRNA selectively targeted the inflamed endothelium of the hemorrhagic brain, resulting in significant reductions in hematoma volume and robust improvements in motor function. Distinct from AIS, VCAM T-NC therapy in ICH did not merely decrease macrophage counts but shifted their phenotype, promoting neuroprotective M2 polarization, as confirmed by molecular and behavioral analyses. Thus, VCAM-targeted nanocarriers represent a versatile, mechanism-tailored platform for neurovascular drug delivery. They enable precision interventions in AIS via selective BBB targeting, suppression of inflammation, and reduced immune cell infiltration, while in ICH, they mediate immunomodulatory phenotype shifts among macrophages for tissue protection and recovery.

The status of extracellular vesicles as drug carriers and therapeutics

Nature Reviews Bioengineering · 2026-02-05 · 5 citations

Manuscript DMD-D-25-00346 The impact of glycocalyx on partitioning and distribution of basic drugs

Drug Metabolism and Disposition · 2026-03-03

Biomechanical and Functional Features of the Carrier Erythrocytes Prolonging Circulation Time of Biotherapeutic Targeted to Glycophorin A

Bioconjugate Chemistry · 2025-01-27 · 4 citations

Red blood cells (RBCs) serve as natural transporters and can be modified to enhance the pharmacokinetics and pharmacodynamics of a protein cargo. Affinity targeting of Factor IX (FIX) to the RBC membrane is a promising approach to improve the (pro)enzyme's pharmacokinetics. For RBC targeting, purified human FIX was conjugated to the anti-mouse glycophorin A monoclonal antibody Ter119. The goal of this study was to characterize the activity of the FIX-Ter119 conjugate and efficacy of its loading on RBCs, as well as to investigate the biodistribution, pharmacokinetics, and various biological properties of the loaded RBCs. Mouse RBCs were incubated with the Ter119-FIX conjugate, where adding 10,000 molecules per RBC resulted in 37% binding (4K/RBC), and 50,000 molecules per RBC resulted in 34% binding (17K/RBC). The pharmacokinetics (PK) profile showed that more than 90% of the Ter119-FIX conjugate was associated with RBCs and circulated stably bound to the RBCs for 24 h, increasing the area under the PK curve 7.6 times vs free FIX. Ter119-FIX loaded RBCs have specific procoagulant FIXa activity, including promotion of thrombin generation and acceleration of clotting in FIX-deficient plasma. Morphological characterization shows that Ter119-FIX-loaded RBCs undergo a shape change, with an increased fraction of echinocytes and spheroidal RBCs. Ektacytometry and electron microscopy assessment of RBC compressibility reveal a dose-dependent reduction in the deformability of RBCs loaded with Ter119-FIX. In conclusion, RBCs loaded with Ter119-FIX have the potential to serve as prohemostatic agents, but their reduced deformability warrants further engineering of Ter119-FIX to improve the safety profile.

Pharmacokinetic and Pharmacodynamic Modeling of Antibody-Drug Conjugates

Cancers · 2025-12-19 · 5 citations

Antibody-drug conjugates (ADCs) have risen in prominence over the past 15 years, with numerous regulatory approvals in oncology. A complicating factor in the development of ADCs is the presence of numerous analytes with unique pharmacologic properties. Following administration, ADCs are present in the body as the intact ADC, unconjugated antibody, and liberated payload. Due to heterogeneity in conjugation and in vivo deconjugation rates, the drug-to-antibody ratio (DAR) changes with time. Each of these molecular species has unique pharmacokinetic (PK) and pharmacodynamic (PD) properties that should be understood and characterized. One approach that is frequently applied is the development of in silico mathematical models to characterize and predict the PK/PD of ADCs. In this review, we summarize key mechanisms controlling the PK/PD of ADCs. This provides context for a detailed discussion of the array of PK/PD models that have been applied for ADCs, ranging from empirical compartmental models all the way through system-level models, such as physiologically based pharmacokinetics (PBPK) and cell-level PK/PD models. We provide a critical discussion of the strengths, weaknesses, and utility of each of these model structures.

Pharmacology of next generation therapeutics

Journal of Pharmacology and Experimental Therapeutics · 2025-12-01

Systemic delivery of biotherapeutic RNA to the myocardium transiently modulates cardiac contractility in vivo

Proceedings of the National Academy of Sciences · 2025-07-16 · 10 citations

Lipid nanoparticles (LNP) represent a versatile platform for improving delivery of therapeutic nucleic acids. Yet, delivery to the myocardium remains a formidable challenge due to local barriers in the heart and systemic hindrances. In particular, plasma apolipoprotein E (apoE) directs LNP to the liver, limiting potential extrahepatic delivery. Here, we report a cardiotropic LNP (cLNP), which within 30 min post–intravenous injection accumulates in the heart of ApoE knockout ( Apoe −/− ) mice. The findings were confirmed for Apoe −/− rats and for wild-type mice after siRNA-mediated plasma apoE ablation. To test cardiac-specific functional effects as a proof of concept, we used cLNP loaded with siRNA to ATP2A2, encoding the sarcoplasmic-endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2A). This cardiomyocyte-specific protein is a key regulator of contractility and relaxation. Intravenous administration of cLNP/siRNA-ATP2A2 in Apoe −/− mice led to near-complete ablation of SERCA2A in the myocardium and a potent modulation of contractility of the cardiomyocytes obtained from these mice. In summary, cardiotropic nanocarriers may allow the delivery and effect of RNA and other agents to the myocardium. Achieving this unmet medical need promises new types of treatment for heart diseases, which remains the leading cause of death worldwide.

VCAM-Targeted Nanocarriers: Transforming the Brain's Vasculature into a Therapeutic Biofactory

Neurotherapeutics · 2025-07-01

We have developed Vascular Cellular Adhesion Molecule (VCAM)-targeted nanocarriers (T-NCs) as a promising platform for drug delivery to the brain, particularly in acute neurovascular inflammation (stroke). These T-NCs demonstrate superior targeting to the blood-brain barrier (BBB), offering significant advantages in drug delivery and therapeutic efficacy. VCAM T-NCs show high specificity for the BBB under inflammatory conditions, achieving 20 times higher uptake than untargeted IgG control T-NCs and up to 100-fold higher delivery vs.

Half-life extension of therapeutics: Applications and mechanisms

Journal of Pharmacology and Experimental Therapeutics · 2025-12-01 · 3 citations

Translational Pharmacokinetic/Pharmacodynamic Modeling of Targeted mRNA-LNP Therapeutics

Journal of Pharmacology and Experimental Therapeutics · 2024-05-13