About

Vladimir R. Muzykantov, MD, PhD, is the Founders Professor in Nanoparticle Research at the University of Pennsylvania School of Medicine. He is a member of multiple research institutes within the university, including the Institute of Medical Engineering, the Center for Cancer Pharmacology, the Institute for Translational Medicine and Therapeutics, the Center for Environmental Toxicology, and the Cardiovascular Institute. He also serves as Vice-Chair for Faculty Development in the Department of Pharmacology. His research expertise encompasses drug and gene targeting, vascular biology, and endothelial cell surface antigens. His work focuses on recognition of surface antigens on normal and pathologically altered endothelial cells, mechanisms of vascular inflammation, oxidative stress, and antioxidant protection of the endothelium. Muzykantov's laboratory develops strategies for controlled, site-specific delivery of therapeutic agents to the pulmonary endothelium, utilizing carrier antibodies and derivatives that recognize specific endothelial surface molecules such as ACE, thrombomodulin, ICAM, PECAM, and selectins. He explores the use of red blood cells as natural carriers for drugs, aiming to prolong circulation time and enable targeted delivery, particularly for fibrinolytics and anticoagulants. His contributions include characterizing cellular trafficking of targeted agents, developing conjugation methodologies for drug delivery via red blood cells, and investigating mechanisms of intracellular targeting and trafficking of drugs. His research aims to improve therapeutic efficacy and safety in conditions such as pulmonary embolism, deep vein thrombosis, and pulmonary pathophysiology, with a focus on nanomedicine, targeted therapeutics, and vascular drug delivery systems.

Research topics

• Cancer research
• Medicine
• Biology
• Immunology
• Internal medicine
• Cell biology

Selected publications

• Targeting DNA‐LNPs to Endothelial Cells Improves Expression Magnitude, Duration, and Specificity

  Advanced Science · 2026-01-20 · 1 citations

  articleOpen access

  DNA-lipid nanoparticles (DNA-LNPs) loaded with inhibitors of the cGAS-STING pathway enable safe and effective delivery of DNA in vivo. Herein, we report the first instances of extrahepatic DNA-LNP targeting. DNA-LNPs conjugated to antibodies against PECAM-1 or VCAM-1 target the endothelium of the lungs and brain/spleen, respectively. These LNPs drive robust transgene expression in their target organs, with greater magnitude and duration than untargeted LNPs. Lung specificity of PECAM-targeted transgene expression increases over two weeks, resulting in markedly higher lung-to-liver expression ratios than our previous PECAM-targeted mRNA-LNPs. Off-target liver DNA expression declines to undetectable levels but persists in the lungs, while mRNA expression uniformly decreases due to its short half-life. We further improve this expression specificity by replacing full-length antibodies with Fab fragments. Single-cell analysis reveals a key mechanism underlying the improvements in organ-specificity: target organ expression is dominated by long-lived endothelial cells, while off-target liver delivery and expression are in non-endothelial cells with shorter half-lives. Collectively, these studies demonstrate that targeted DNA-LNPs achieve high levels of organ- and cell-type-specific transgene expression and thus provide a therapeutic platform for dozens of endothelial-centric diseases.

  PublisherDOI

• Decoupling Physisorption from Chemisorption in Clickable Lipid Nanoparticles

  ACS Nanoscience Au · 2026-02-20

  articleOpen accessCorresponding

  Antibody conjugation is essential for targeted lipid nanoparticle (LNP) delivery, but here we show that click-chemistry produces artifacts that confound accurate measurement of covalent antibody-LNP bonding. We demonstrate that hydrophobic interactions between the most common click alkyne linker, dibenzocyclooctyne (DBCO), and the inherently hydrophobic LNP surface drive extensive nonspecific antibody physisorption, even in the absence of LNP azide groups. This physisorption yields artificially high apparent conjugation efficiencies measured by chromatographic methods. In contrast, less hydrophobic liposomes exhibit azide-dependent conjugation, highlighting a consequence of nanoparticle surface chemistry. Plasma incubation rapidly displaces physisorbed antibodies from LNPs, confirming their weak, noncovalent association, whereas covalently bound antibodies remain attached and enable effective in vivo targeting. Substituting DBCO with the less hydrophobic bicyclononyne (BCN) also reduces nonspecific associations. Our findings reveal hydrophobicity as a hidden variable in antibody–LNP conjugation and establish new standards for quantitative and reproducible measurement of targeted LNPs.

  PublisherDOI

• Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

  Nature Nanotechnology · 2025-08-11 · 42 citations

  articleOpen access
  PublisherOA PDFDOI

• Abstract 4362907: Inhibition of Fibrin Formation by the GPRP–Dextran Conjugate: A New Approach to Safe Anticoagulation

  Circulation · 2025-11-03

  articleSenior author

  Introduction: Fibrin formation begins with the thrombin-catalyzed cleavage of fibrinopeptide A from fibrinogen followed by exposure of the Gly-Pro-Arg(GPR) sequence called knob 'A'. This motif interacts with complementary holes ‘a’ in other fibrin molecules, driving fibrin polymerization. The GPRP peptide mimics knob 'A' and blocks competitively the knob-hole interactions, inhibiting fibrin assembly. Interruption of fibrin formation represents a novel strategy for anticoagulation to prevent or attenuate thrombosis. Hypothesis: The synthesized GPRP-dextran conjugate possesses anticoagulant activity in vitro and in vivo . Methods: GPRP was attached covalently to dextran to prolong its circulation time. The anticoagulant activity of the conjugate was assessed via aPTT and ROTEM in human PFP. Fibrin polymerization was evaluated by dynamic turbidimetry and clottable fibrinogen levels. Fibrin clot structure was analyzed using scanning electron microscopy (SEM) and fluorescent confocal microscopy. In vivo effects were studied in mice after intravenous injection of the conjugate, followed by bleeding time analysis and ex vivo blood clotting assays. Results: GPRP–dextran significantly prolonged aPTT and changed the ROTEM parameters, including prolonged clotting time, reduced clot strengthening rate and clot firmness. The GPRP-dextran conjugate suppressed fibrin polymerization in a dose-dependent manner with an IC50 of ~ 40μM and reduced the clottable fibrinogen level, indicating that the conjugate can be used to push the equilibrium toward dissociation, without entirely abrogating clotting. SEM revealed that fibrin formed in the presence of GPRP–dextran was structurally abnormal with shortened and thickened fibers with barbed ends and clusters. Confocal microscopy confirmed these observations, showing disrupted fibrin networks and decreased fiber branching density in the GPRP-dextran-containing samples. After intravenous injection in mice and 15 minutes of circulation, ex vivo testing demonstrated a notable reduction in clottable fibrinogen levels. Importantly, the treatment did not prolong significantly tail bleeding time, indicating that the anticoagulant effect did not compromise hemostatic safety. Conclusion: GPRP–dextran exhibits anti-fibrin polymerization effects in vitro and in vivo , highlighting its potential as a novel anticoagulant and antithrombotic agent with minimal bleeding risk. This work was supported by American Heart Association grant#25POST1357254.

  PublisherDOI

• Tailoring the adjuvanticity of lipid nanoparticles by PEG lipid ratio and phospholipid modifications

  Nature Nanotechnology · 2025-06-23 · 33 citations

  articleOpen access
  PublisherOA PDFDOI

• Modeling Fibrosis with MASH Patient Liver-Derived Organoids

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-21 · 1 citations

  preprintOpen access

  Summary Metabolic dysfunction-associated steatohepatitis (MASH) can lead to liver fibrosis and cirrhosis ultimately leading to liver transplantation or death. Therapeutic options for MASH-associated fibrosis are limited in part because of the lack of good model systems. To address this challenge, we developed a 3D MASH liver fibrosis model by using organoids derived from MASH patient liver co-cultured with human liver-derived hepatic stellate cells (HSC) and human peripheral blood monocytes (MC). Spontaneous self-assembly resulted in fibrotic scar-like 3D structures with senescent parenchymal cells, proliferating collagen secreting myofibroblasts (MFB) and proinflammatory TREM2+ scar-associated macrophages (MP). Single cell RNA sequencing suggested high similarity with MASH patient liver fibrotic scars. Lipid nanoparticles (LNPs) formulated with anti- YAP1 siRNA could specifically and efficiently knockdown YAP1 in the MFBs, resulting in MFB senescence, a desirable therapeutic goal. This MASH patient liver-derived fibrosis model opens novel avenues towards testing treatments for MASH-associated liver fibrosis with reduced adverse effects.

  PublisherDOI

• 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

  articleOpen accessSenior authorCorresponding

  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.

  PublisherDOI

• Abstract TP368: Targeted Lipid Nanoparticles to Modulate Blood-Brain Barrier Transcytosis in Acute Ischemic Stroke

  Stroke · 2025-01-30

  articleSenior author

  Ischemic stroke affects more than 600,000 Americans annually. Thrombectomy, where occluded arteries are cannulated for mechanical clot removal, can restore blood flow and improve survival, but still leaves 1/3 of patients functionally dependent, largely due to secondary ischemia-reperfusion injury. Brain edema in the acute phase of ischemia-reperfusion primarily associates with early-stage neurovascular damage and plays a major role in poor outcomes of stroke. Early on after ischemia/reperfusion, edema is mediated by increased transcytosis in the blood brain barrier (BBB) endothelium. Suppression of transcytosis has not yet been tested as a treatment for stroke. Major facilitator superfamily domain containing 2a (Mfsd2a) is a transporter protein that regulates caveolar transcytosis and is downregulated in ischemic stroke. We have previously demonstrated that 1) lipid nanoparticles loaded with mRNA (mRNA/LNP) enable rapid and robust protein expression; 2) vascular cell adhesion molecule (VCAM) targeting selectively delivers nanoparticles to stroke-affected BBB endothelium; 3) mRNA/LNP targeted to VCAM enabled protein expression in BBB endothelium. Therefore, we hypothesize that using LNPs containing Mfsd2a mRNA and targeted to vascular cell adhesion molecule (VCAM) can modulate Mfsd2a expression in inflamed BBB and improve outcome in ischemic stroke. In this work, we screened 10 LNP formulations and identified the optimized formulation on bEND.3 brain endothelial cells for Mfsd2a expression. The induction of Mfsd2a expression significantly enhanced Cav-1 expression and reduced the number of apical caveolae-formations by electron microscopy. Next, we used the acute ischemic stroke animal model (transient middle cerebral artery occlusion for 45 minutes) to assess the therapeutic outcome of VCAM-targeted LNP loaded with Mfsd2a mRNA. Right after reperfusion, we intravenously injected LNP and two additional dose every 24 hours (8ug RNA per dose). On day 3, we assessed brain edema by measuring the extravasation of radiolabeled albumin into the brain parenchyma. The percent of the extravasated albumin was significantly reduced after LNP treatment. In addition, using transmission electron microscopy, we observed less number of caveolae in the treated mice, compared to vehicle control. In conclusion, we have showed that VCAM targeted LNPs are able to deliver Mfsd2a mRNA to the inflamed brain vasculature and reduce brain edema by suppression of transcytosis.

  PublisherDOI

• CD47 peptide-cloaked lipid nanoparticles promote cell-specific mRNA delivery

  Molecular Therapy · 2025-03-13 · 26 citations

  articleOpen access

  mRNA-based therapeutics delivered via lipid nanoparticles (LNP-mRNA) hold great promise for treating diverse diseases. However, further improvements are needed to refine outcomes in non-vaccine, extrahepatic applications, such as minimizing the rapid clearance and off-target uptake in undesired tissues of the mononuclear phagocyte system (MPS). We propose modifying LNP surfaces with the phagocytic cell "don't eat me" signal, CD47, in combination with our previously established antibody-based targeted LNP (tLNP) to create a CD47/tLNP platform with reduced phagocytic clearance and off-target effects and improved efficiency for cell-specific delivery. We showed that CD47 modification decreased macrophage and hepatic uptake both in vitro and in vivo. Combining CD47 modification with antibodies targeting endothelial cells, T cells, or hematopoietic stem cells (HSCs) increased targeting efficiency up to 3-fold compared to tLNP alone. Enhanced targeting of CD47/tLNP to HSCs with reduced off-targeting enabled the delivery of pro-apoptotic mRNA for HSC depletion as a preconditioning strategy prior to bone marrow transplant. Additionally, CD47-modified LNPs showed diminished inflammatory effects on hepatic tissue and an altered protein corona. Our CD47/tLNP-mRNA platform, with its reduced phagocytic clearance, mitigated inflammatory effects, and enhanced targeted delivery, should further facilitate the development of in vivo mRNA therapeutics.

  PublisherDOI

• Core-Then-Shell Lipid Nanoparticles for Next Generation Nucleic Acid Delivery: Improving Gene Delivery by Enhanced DNA Encapsulation (Abstract ID: 158560)

  Journal of Pharmacology and Experimental Therapeutics · 2025-03-01

  article
  PublisherDOI

Recent grants

• NIH Grant R01HL116916

  NIH · $1.2M · 2018

• Dual drug delivery to lung/blood interface in respiratory infections.

  NIH · $2.9M · 2021–2025

• Vascular Targeting of Nanocarriers for RNA

  NIH · $3.1M · 2021–2026

• NIH Grant R01HL11691601

  NIH · $397k · 2017

• Controlling complement to unleash nanomedicine for acute critical illnesses

  NIH · $2.0M · 2022–2026

Frequent coauthors

• Vladimir V. Shuvaev

  Translational Therapeutics (United States)

  279 shared

• Colin F. Greineder

  University of Michigan–Ann Arbor

  259 shared

• С. В. Зайцев

  205 shared

• Douglas B. Cines

  University of Pennsylvania

  195 shared

• Oscar A. Marcos‐Contreras

  University of Pennsylvania

  183 shared

• Jacob S. Brenner

  California University of Pennsylvania

  178 shared

• Bi‐Sen Ding

  173 shared

• Elizabeth D. Hood

  Translational Therapeutics (United States)

  167 shared

Labs

• Systems Pharmacology and Translational TherapeuticsPI