About

Norbert Pardi, PhD, is an Associate Professor of Microbiology at the University of Pennsylvania's Perelman School of Medicine. He is the Vaccines Group Lead at the Penn Institute for RNA Innovation. His research expertise includes mRNA therapeutics, with a focus on vaccine development and immunological assays. Dr. Pardi has contributed to the development of mRNA-lipid nanoparticle vaccines, including those targeting Lyme disease and SARS-CoV-2, and has published extensively on the efficacy and stability of mRNA vaccine components. His work involves enhancing prime editor activity, antibody-independent protection against SARS-CoV-2, and exploring the effects of mRNA vaccination on various biological processes.

Research topics

• Biology
• Immunology
• Virology
• Genetics
• Medicine
• Biochemistry
• Computer Science
• Internal medicine
• Computational biology
• Molecular biology

Selected publications

• RNA-LNP–mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I

  Science Translational Medicine · 2026-05-13

  article

  Citrullinemia type I (CTLN1) is a severe urea cycle disorder caused by pathogenic variants in the ASS1 (argininosuccinate synthetase 1) gene, for which liver transplantation remains the only curative option. Here, we used prime editing to correct the Ass1 fold mouse model of CTLN1. Adeno-associated virus (AAV)–mediated delivery of the PE7 prime editor with an optimized prime editing guide RNA (pegRNA) achieved 71 and 54% correction of the pathogenic Ass1 mutation in hepatocytes of neonates and juveniles, respectively. Delivery of mRNA-encoded PE7 and synthetic pegRNA via lipid nanoparticles (LNPs) resulted in 24% correction after a single 3 mg kg −1 dose in neonates and 13% after three 4 mg kg −1 doses in juveniles. All treated groups showed full normalization of survival and of blood citrulline and ammonia concentrations, with restored urea cycle function and correction of natural behavior defects. Consistent with these findings, immunostaining demonstrated restoration of wild-type–like ASS1 protein localization in functionally relevant periportal and intermediate-zone hepatocytes. Editing was confined to the liver, with minimal indel formation and off-target activity and only transient elevations in liver enzymes. In a cellular reporter system, 6 of 15 recurrent human pathogenic ASS1 mutations studied, including the most common ASS1 G390R variant, were corrected with similar or higher efficiencies than Ass1 fold . These findings highlight prime editing as a precise and potentially curative treatment strategy for individuals with CTLN1 and other genetic liver diseases.

  PublisherDOI

• Abstract 5560: KRASG12Dinhibition stimulates antigen presentation and potentiates mRNA-based immunotherapy in pancreatic cancer

  Cancer Research · 2026-04-03

  article

  Abstract Inhibition of constitutively-active KRASG12D, a powerful oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), has been shown to sensitize tumors to T-cell-mediated immunotherapy in preclinical models. However, the influence of KRASG12D inhibition on tumor cell antigen presentation remains unclear. Therefore, we employed a multi-omic profiling workflow to investigate alterations in the proteome and peptide MHC-I ligandome (immunopeptidome) following the treatment of HPAC human cancer cells with a RAS(ON) G12D-selective inhibitor RMC-9945 (representative of investigational agent zoldonrasib), and/or IFNɣ in vitro. KRASG12D inhibition induced a unique IFN response signature and potentiated the expression of proteins involved in antigen processing and presentation. Immunopeptidomic analysis revealed a two-fold increase in both ligand abundance and diversity, reflecting the differential expression of proteins induced by KRASG12D inhibition. We hypothesized that KRASG12D signaling inhibition in preclinical models could augment immune responses initiated by immunization targeting tumor antigens in vivo via the following mechanism: the release of antigens from KRASG12D-induced cell death, coupled with increased MHC-I expression on remaining tumor cells, would enhance interactions with T cells activated by immunization. To test this, we orthotopically inoculated C57Bl/6 mice with a murine PDAC-KRASG12D cell line engineered to express the model self/tumor-associated antigen gp100. Mice were then immunized with either empty ionizable lipid nanoparticles (e-iLNPs) or iLNPs packaged with mRNA encoding full-length gp100 (gp100-iLNP). Prior to and during subsequent vaccine boost doses, mice were treated continuously with either KRASG12D inhibitor RMC-9945 or vehicle. Mice treated with both gp100 mRNA-iLNP immunization and KRASG12D inhibition exhibited significant tumor regression that was sustained over time compared to either treatment modality alone. This anti-tumor response was associated with a superior antigen-specific T cell response to subsequent immunizations, the retention of functional tumor antigen-specific cytotoxic T lymphocytes in both the tumor microenvironment and local secondary lymphoid organs, and sustained MHC-I and MHC-II surface expression on tumor cells. These preclinical findings underscore the dynamic nature by which PDAC antigen presentation can be modulated by KRAS signaling inhibition and IFNɣ. Combining allele-specific KRAS inhibition with tumor antigen immunization resulted in sustained tumor regression in vivo and was associated with the retention and function of tumor antigen-specific T cells. This rationalizes the combination of both approaches for enhanced anti-tumor activity, offering a strategy that is worth exploring clinically for improving outcomes in pancreatic cancer treatment. Citation Format: Amanda Creech, Hailey Lee, Khalid Rashid, Tony Luu, Emma Lieberman, Michael Srienc, Alykhan Premji, Ahmad Kassem, Luyi Li, James Wohlschlegel, Timothy Donahue, Norbert Pardi, Caius Radu. KRASG12Dinhibition stimulates antigen presentation and potentiates mRNA-based immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5560.

  PublisherDOI

• Immunotherapy against colorectal cancer via delivery of anti-PD-L1 nanobody mRNA

  eGastroenterology · 2025-07-01 · 1 citations

  letterOpen access

  Background Monoclonal antibodies (mAbs) targeting immune checkpoint molecules such as programmed death ligand 1 (PD-L1), which is expressed in both immune and tumour cells, are conventional immunotherapy approaches. Although approved as monotherapy for the first-line treatment of several cancers, mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer (CRC). Here, we investigated if nucleic acids translated into anti-PD-L1 nanobodies (PDL1Nbs) effectively suppress CRC tumourigenesis in mouse models. Methods Mice were transplanted with MC-38 mouse sporadic CRC (sCRC) cells or challenged with azoxymethane and dextran sodium sulfate, a combination treatment that induces colitis-associated CRC (CAC). The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA (pDNA) delivered via polymers, or treated with PDL1Nb-encoding nucleoside-modified messenger RNA (PDL1Nb mRNA) delivered via lipid nanoparticles (LNP). Moreover, bone marrow haematopoietic stem cells (BMHSCs) were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide. We examined sCRC tumour proliferation and growth, CAC tumour incidences and numbers, tumour infiltration of immune cells and bone marrow-derived macrophages (BMDMs). Results Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice. Intriguingly, LNP delivery of the quadruple PDL1Nb (qPDL1Nb) mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb (mPDL1Nb) mRNA in suppressing sCRC tumour progression. Moreover, qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence. Mechanistically, PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages, as well as expression of PD-L1, but increases in tumour-infiltrating CD3 + CD8 + cells during CAC tumourigenesis . Notably , in vitro LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1, CD80, CD86 and CD206 in BMDMs. Conclusion These results suggest that the PDL1Nb therapy is effective for both CAC and sCRC and using qPDL1Nb mRNA-LNP is a promising alternative strategy for CRC immunotherapy.

  PublisherOA PDFDOI

• Predicting adenine base editing efficiencies in different cellular contexts by deep learning

  Genome biology · 2025-05-08 · 4 citations

  articleOpen access

  BACKGROUND: Adenine base editors (ABEs) enable the conversion of A•T to G•C base pairs. Since the sequence of the target locus influences base editing efficiency, efforts have been made to develop computational models that can predict base editing outcomes based on the targeted sequence. However, these models were trained on base editing datasets generated in cell lines and their predictive power for base editing in primary cells in vivo remains uncertain. RESULTS: In this study, we conduct base editing screens using SpRY-ABEmax and SpRY-ABE8e to target 2,195 pathogenic mutations with a total of 12,000 guide RNAs in cell lines and in the murine liver. We observe strong correlations between in vitro datasets generated by ABE-mRNA electroporation into HEK293T cells and in vivo datasets generated by adeno-associated virus (AAV)- or lipid nanoparticle (LNP)-mediated nucleoside-modified mRNA delivery (Spearman R = 0.83-0.92). We subsequently develop BEDICT2.0, a deep learning model that predicts adenine base editing efficiencies with high accuracy in cell lines (R = 0.60-0.94) and in the liver (R = 0.62-0.81). CONCLUSIONS: In conclusion, our work confirms that adenine base editing holds considerable potential for correcting a large fraction of pathogenic mutations. We also provide BEDICT2.0 - a robust computational model that helps identify sgRNA-ABE combinations capable of achieving high on-target editing with minimal bystander effects in both in vitro and in vivo settings.

  PublisherOA PDFDOI

• Enhancing functional antibody responses against HIV envelope V1V2 through vaccine formulations

  Frontiers in Immunology · 2025-12-08

  articleOpen access

  Background: Despite decades of research, the development of an effective HIV vaccine remains a significant challenge. Recent findings from three large vaccine efficacy trials have identified antibodies against the V1V2 domain of the HIV envelope glycoprotein as a potential correlate of reduced infection risk, offering a promising avenue for improving vaccine efficacy. Vaccine-elicited anti-V1V2 antibodies do not mediate potent virus-neutralizing activities, but they mediate Fc-dependent effector functions. Methods: This study evaluated the capacity of V1V2-scaffold vaccines in different formulations to generate antibody responses with Fc-mediated functions. BALB/c mice were immunized with V1V2-scaffold proteins formulated with one of the following adjuvants: MF59-like squalene-based oil-in-water emulsion (Addavax), a combination of TLR7/8 and RIG-I agonists (IMDQ-PC/IVT), nanoemulsion and RIG-I agonist (NE/IVT), or empty lipid nanoparticles (eLNP). All formulations were administered intramuscularly except NE/IVT, which was given intranasally. For comparison, we also tested a V1V2-scaffold-expressing mRNA-LNP vaccine delivered intramuscularly and an Env gp140 protein with liposomal MPLA/DDA adjuvant administered subcutaneously. Results: Among the six vaccine formulations tested, V1V2-scaffold immunogens adjuvanted with LNP (eLNP and mRNA-LNP) elicited the most robust and cross-reactive serum IgG responses that recognized native Env on cell surfaces or virions. The eLNP and mRNA-LNP groups, along with IMDQ-PC/IVT, also elicited functional IgG2a, and correspondingly displayed Fc-mediated activities, as measured by antibody-dependent cellular phagocytosis and FcγRIV binding. Notably, IMDQ-PC/IVT elicited predominantly IgG2a with minimal IgG1, eLNP stimulated IgG1 and IgG2a with IgG1 dominance, whereas mRNA-LNP yielded more balanced IgG2a/IgG1 responses. Conclusions: Data from this study provide new insights into the utility of novel formulations for V1V2-scaffold immunogens as a strategy for optimizing the induction of functional V1V2-specific antibodies to improve HIV vaccine efficacy.

  PublisherOA PDFDOI

• Clinical advances in gene, cell, and RNA therapies

  Molecular Therapy · 2025-05-20

  editorial
  PublisherDOI

• mRNA-LNP vaccines against Hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-14

  preprintOpen accessCorresponding

  Abstract Over 300 million people worldwide suffer from chronic hepatitis B virus infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic disease. This study investigated lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines encoding Hepatitis B surface antigen (HBsAg) for prophylactic and therapeutic applications. We found that HBsAg mRNA-LNP vaccines induced robust humoral and cellular immune responses, outperforming the protein-based vaccine approved for human use. The incorporation of an MHC class I signal peptide further enhanced Th1-biased responses preventing HBV infections in a mouse model. Importantly, mRNA-LNP vaccination led to seroconversion, HBsAg clearance, and strong T cell responses in a chronically infected mouse model. These findings highlight the potential of mRNA-LNP as an alternative and effective vaccine modality for HBV prophylaxis and therapeutic use in treating chronic infections.

  PublisherOA PDFDOI

• Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

  Cell Reports Medicine · 2025-09-25 · 2 citations

  articleOpen access

  A universal influenza vaccine that elicits a strong and lasting stalk-specific antibody response is advantageous. We utilize nucleoside-modified mRNA in lipid nanoparticles (mRNA-LNP) and unmodified self-amplifying mRNA in modified dendritic nanoparticles (sam-MDNP), expressing chimeric hemagglutinin (cHA) antigens to induce stalk-specific humoral immunity in non-human primates with pre-existing influenza virus immunity. mRNA-LNP immunization induces strong stalk-specific binding antibodies capable of protecting mice from lethal heterologous influenza virus challenges and bone marrow plasma cells (BMPCs) that persist for up to 8 months. sam-MDNP vaccine induces lower humoral immunity, despite showing strong innate activation. Transcriptomic and cytokine analyses reveal a more persistent induction of interferon responses, interleukin (IL)-1β signaling, and IL-6 production in the mRNA-LNP group, correlating with the induction of serum antibody responses and BMPCs. These results identify a transcriptional signature associated with induction of BMPCs following mRNA vaccination and highlight the utility of cHA-based mRNA-LNP vaccines in inducing persistent stalk-directed protective antibody responses.

  PublisherDOI

• Homologous and Heterologous Vaccination Regimens with mRNA and rVSV Platforms Induce Potent Immune Responses Against SFTSV Glycoprotein

  Viruses · 2025-08-08 · 7 citations

  articleOpen access

  BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic bunyavirus with a high case-fatality ratio for which there is no approved vaccine. Studies have assessed different vaccine technologies. However, few studies have yet assessed the immunogenicity of heterologous prime-boost regimens. METHODS: Here, we compare a lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA-based vaccine encoding the SFTSV glycoproteins, Gn and Gc, to our recently described recombinant VSV SFTSV (rVSV-SFTSV) vaccine in single dose, homologous, and heterologous prime-boost regimens in mice. RESULTS: We show that all regimens protect from pathogenic SFTSV challenge and elicit strong long-lasting antibody responses. Furthermore, strong cellular immunity is elicited by mRNA-LNP immunizations and by heterologous immunization with an rVSV-SFTSV prime and mRNA-LNP boost. Cellular responses robustly polarized towards a type 1 response, characterized by high levels of IFNγ, TNFα, and IL-2. Immunization with mRNA led to a mixed type 1/type 2 immune response, as determined by antibody isotypes IgG1 and IgG2c. We found that homologous immunization leads to stronger antibody responses while heterologous immunization drives a slightly stronger cellular response. CONCLUSIONS: Taken together, the vaccine platforms described here represent strong vaccine candidates for further development.

  PublisherOA PDFDOI

• 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 access

  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

Recent grants

• Development of Universal Influenza Virus Vaccines Using Nucleoside-Modified Messenger RNA

  NIH · $2.4M · 2019–2024

• Development of Universal Influenza Virus Vaccines Using Nucleoside-Modified Messenger RNA

  NIH · $641k · 2019–2024

• Lipid nanoparticle adjuvants for mRNA vaccines: composition-function relation and mechanism of action

  NIH · $3.4M · 2020–2030

Frequent coauthors

• Drew Weissman

  University of Pennsylvania

  81 shared

• Hiromi Muramatsu

  University of Pennsylvania

  62 shared

• Brian D. Quinlan

  University of Florida

  57 shared

• Ying K. Tam

  Acuitas Therapeutics (Canada)

  55 shared

• Lizhou Zhang

  Yanshan University

  51 shared

• Michael Farzan

  Harvard University

  51 shared

• Amrita Ojha

  Stanford University

  51 shared

• Hao Li

  South China Normal University

  49 shared

Labs

• Vaccines Group, Perelman School of Medicine, University of PennsylvaniaPI

Education

• Ph.D., Biochemistry and Genetics

  University of Szeged, Hungary

  2011

• M.S., Biochemistry and Genetics

  University of Szeged, Hungary

  2004