About

Jilian R Melamed, PhD, is a Research Assistant Professor of Medicine in the Department of Medicine at the University of Pennsylvania's Perelman School of Medicine. Her research expertise includes RNA therapeutics, nanomedicine, and drug delivery. Dr. Melamed's work focuses on delivering mRNA to pancreatic beta cells via macrophage-mediated gene transfer using ionizable lipid nanoparticles. Her contributions include developing lipid nanoparticles with specific tropisms, modulating mRNA-lipid nanoparticle immunogenicity, and exploring their applications in autoimmune diseases, cancer, and allergy treatments. She has authored numerous publications on high-throughput in vivo screening, nanoparticle targeting, and immunoengineering, advancing the understanding of nanomedicine and RNA-based therapies.

Research topics

• Genetics
• Biochemistry
• Cell biology
• Molecular biology
• Biology
• Chemistry

Selected publications

• Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy

  Nature Nanotechnology · 2026-03-01

  article
  PublisherDOI

• Abstract A055: Restoring the Blood-Brain Barrier after Stroke: VCAM-Targeted MFSD2A mRNA Nanoparticle Therapy with Functional Recovery

  Stroke · 2026-01-29

  article

  Ischemic stroke remains a leading cause of death and disability in the United States. Although interventions such as tissue plasminogen activator and mechanical thrombectomy have improved acute outcomes, many patients experience long-term deficits due to secondary ischemia-reperfusion injury. Blood-brain barrier (BBB) disruption, particularly via increased endothelial transcytosis, is a key pathological contributor to these outcomes. Our RNA-seq analysis at 24 hours post-transient middle cerebral artery occlusion (tMCAO) revealed increased expression of caveolin-1 and decreased β-catenin levels, changes associated with enhanced vesicular transcytosis and BBB breakdown compared to sham controls. These findings identify Major Facilitator Superfamily Domain Containing 2a (MFSD2A) as a critical modulator of BBB integrity, as MFSD2A inhibits caveolin-1–mediated transcytosis and is positively regulated by β-catenin signaling. Targeted nanoparticle delivery offers a promising strategy to improve therapeutic specificity in brain diseases, including ischemic stroke. Vascular cell adhesion molecule (VCAM), upregulated during neuroinflammation, serves as an effective target for drug delivery to ischemic vasculature. Our laboratory demonstrated that VCAM-targeted lipid nanoparticles (LNPs) significantly increased brain accumulation of mRNA cargo versus non-targeted controls in multiple disease models, including tMCAO. In this study, we developed VCAM-targeted LNPs encapsulating MFSD2A mRNA (VCAM/MFSD2A) to 1) selectively deliver therapeutics to inflamed cerebral endothelium and 2) restore BBB function. In vitro, VCAM/MFSD2A treatment of bEnd3 cells significantly reduced surface pits indicative of transcytosis inhibition versus untreated cells. In vivo, VCAM/MFSD2A-treated tMCAO mice showed a ~22% increase in survival compared to untreated controls and significantly better survival than the non-targeted IgG/MFSD2A group, which exhibited 40% survival at study end. Treated mice also demonstrated improved neurobehavioral scores on days 1–3 post-stroke. BBB integrity was preserved, as shown by reduced radiolabeled albumin extravasation, and electron microscopy confirmed decreased endothelial caveolae in treated animals. Collectively, these results demonstrate that VCAM/MFSD2A effectively mitigates stroke-induced BBB dysfunction, reduces cerebral edema, and improves neurological recovery. This approach represents a promising therapeutic strategy for enhancing stroke outcomes.

  PublisherDOI

• Decoupling Physisorption from Chemisorption in Clickable Lipid Nanoparticles

  ACS Nanoscience Au · 2026-02-20

  articleOpen access

  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

• High‐Throughput In Vivo Screening Using Barcoded mRNA Identifies Lipid Nanoparticles With Extrahepatic Tropism for In Situ Immunoengineering

  Advanced Materials · 2026-01-28 · 1 citations

  articleOpen access

  Interest continues to grow in the use of mRNA vaccines and therapeutics. While effective for immunization against infectious diseases, lipid nanoparticle (LNP) formulations used for other mRNA delivery applications suffer from off-target accumulation, poor immune transfection, and reactogenicity, limiting their application to immunoengineering. Development of new mRNA LNPs is severely bottlenecked by the LNP discovery process, which is historically low-throughput due to reliance on low-plex measurements. Here, we develop a high-throughput in vivo mRNA LNP screening platform based on barcoded mRNA (b-mRNA). Using this b-mRNA screening platform to simultaneously evaluate 122 LNPs, we identify novel LNP formulations capable of potent hepatic and extrahepatic transfection. We evaluate a lead LNP candidate for in situ immune modulation in a syngeneic mouse model of melanoma and demonstrate a significant reduction in tumor burden and extended survival compared to mice treated with a gold standard mRNA LNP formulation. We employ novel biochemical characterization techniques to analyze nanoparticle protein corona formation with single-particle resolution and gain insight into the influence of protein adsorption on hepatic and splenic transfection. Together, our results demonstrate the value of advanced LNP screening and characterization techniques for the development of next-generation mRNA LNPs for immunoengineering.

  PublisherOA PDFDOI

• High-throughput <i>in vivo</i> screening using barcoded mRNA identifies lipid nanoparticles with extrahepatic tropism for cancer immunotherapy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-09 · 1 citations

  preprintOpen access

  Abstract Interest continues to grow in the use of mRNA vaccines for cancer immunotherapy. While effective for immunization against infectious diseases, current clinical lipid nanoparticle (LNP) formulations used for mRNA delivery suffer from off-target accumulation, poor immune transfection, and reactogenicity, limiting their application to cancer immunotherapy. Development of new mRNA LNPs is severely bottlenecked by the LNP discovery process, which is historically low-throughput due to reliance on low-plexity measurements. Here, we develop a next-generation high-throughput in vivo mRNA LNP screening platform based on barcoded mRNA (b-mRNA). Using this b-mRNA screening platform to simultaneously evaluate 122 LNPs, we identify novel LNP formulations capable of potent hepatic and extrahepatic transfection. We employ novel biochemical characterization techniques to analyze nanoparticle protein corona formation with single-particle resolution and gain insight into the influence of protein adsorption on hepatic and splenic transfection. We evaluate a lead LNP candidate for therapeutic cancer vaccination in a syngeneic mouse model of melanoma and demonstrate a significant reduction in tumor burden and increase in survival compared to a clinical mRNA LNP formulation. Together, our results demonstrate the value of advanced LNP screening and characterization techniques for the development of next-generation mRNA therapeutics and vaccines.

  PublisherOA PDFDOI

• SRSF3 knockdown-induced cellular senescence as a possible therapeutic strategy for non-small cell lung cancer

  Carcinogenesis · 2025-10-01

  article

  Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases account for only about 50% in the western populations. Inhibition of the splicing factor SRSF3 has been reported to be tumor-suppressive in other cancer cell types. This study for the first time explores the tumor-suppressive activity of siRNA knockdown of SRSF3 in NSCLC cells. The cell lines used were A549 (no TK mutation; TP53 wild type), NCI-H1975 (EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant), and NCI-H596 (no TK mutation; TP53 G245C mutant). In all these cell lines, SRSF3 knockdown increased cellular senescence, as indicated by increased senescence-associated β-galactosidase activity and reduced cell proliferation. In A549 cells, increased apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed. A tumor-suppressive p53 isoform, p53β, was shown to be upregulated by SRSF3 knockdown. However, overexpression of p53β did not induce cellular senescence or apoptosis, suggesting that this p53 isoform is not a primary effector of SRSF3 knockdown in NSCLC cells. Gene expression analyses suggested that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by the downregulation of TOP2A, UBE2C, or ASPM, which are known oncogenic factors associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study proposes a therapeutic strategy for NSCLC that is independent of the mutation status of TP53 and TK-encoding genes.

  PublisherDOI

• SRSF3 knockdown-induced cellular senescence as a possible therapeutic strategy for non-small cell lung cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-09 · 2 citations

  preprintOpen access

  Abstract Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases only consist of about 50% in the western populations. This study, for the first time in NSCLC cells including those without a targetable TK mutation, explores a tumor-suppressive activity of siRNA knockdown of a splicing factor SRSF3, which was reportedly effective in other cancer cell types. The knockdown of SRSF3 increased cellular senescence, indicated by senescence-associated β-galactosidase activity and reduced cell proliferation, in all NSCLC cell lines examined, including A549 (no TK mutation; TP53 wild-type), NCI-H1975 ( EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant) and NCI-H596 (no TK mutation; TP53 G245C mutant). An increase in apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed in A549 cells. p53β, a tumor-suppressive p53 isoform generated via alternative mRNA splicing, was upregulated by SRSF3 knockdown, as previously reported in normal fibroblasts. However, neither cellular senescence nor apoptosis was increased by overexpression of p53β, suggesting no or minimum contribution of this p53 isoform to the tumor-suppressive activity of SRSF3 knockdown in NSCLC cells. Our gene expression assay indicated that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by downregulation of TOP2A, UBE2C or ASPM, which are known to be oncogenic and are associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study suggests a therapeutic strategy for NSCLC irrespective of the mutation status of TP53 and TK-encoding genes. Summary Knockdown of a splicing factor SRSF3 increases cellular senescence in NSCLC cells including those with no targetable mutation of tyrosine kinases and thus may represent a novel therapeutic strategy for a hard-to-treat group of NSCLC.

  PublisherOA PDFDOI

• Anionic lipids modulate mRNA-lipid nanoparticle immunogenicity and confer protection in a mouse model of multiple sclerosis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-17 · 3 citations

  preprintOpen access1st author

  ABSTRACT The modularity of mRNA-lipid nanoparticle (mRNA-LNP) platforms has enabled their rapid adaptation from infectious disease vaccines to emerging applications in immune-mediated disorders. However, extending mRNA-LNPs to autoimmune and inflammatory diseases requires precise control over immune cell targeting and immunogenicity. Here, we systematically investigate how incorporating anionic lipids into LNPs modulates both immune cell tropism and innate immune activation. Using a library of 40 distinct LNP formulations, we demonstrate that anionic lipids enhance mRNA delivery to splenic dendritic cells, reduce early cellular markers of adjuvant activity and tune cytokine responses in a lipid-dependent manner. We identify formulations that retain pro-inflammatory adjuvant activity and others that promote tolerogenic responses. A lead formulation containing the anionic lipid DOPG selectively dampens innate activation and induces IL-10 production. When encoding the myelin antigen MOG 35-55 , this LNP suppresses disease in a mouse model of multiple sclerosis, reducing neuroinflammation, T cell infiltration, and maintaining myelin morphology. These findings establish a framework for designing immune-targeted mRNA–LNPs with tunable immunogenicity and promote the development of antigen-specific tolerizing immunotherapies for autoimmune disease.

  PublisherOA PDFDOI

• Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases

  Molecular Therapy — Methods & Clinical Development · 2025-08-18 · 12 citations

  reviewOpen accessSenior author

  chimeric antigen T cell therapies. To successfully advance this promising class of therapies to the clinic, key challenges must be addressed, such as mitigating unwanted inflammation caused by LNPs, overcoming biological barriers to delivery, and ensuring the long-term safety of mRNA-LNPs specifically in autoimmune contexts. Through their modular design, flexible application, and potential for cost-effective production, mRNA-LNP therapies offer exciting clinical potential to transform the management of autoimmune diseases.

  PublisherDOI

• Engineering a Fibrotic Scar Organoid Model for MASH Liver Disease

  Scholarly Commons (University of Pennsylvania) · 2025-09-15

  otherOpen access

  Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive fibrotic liver disease affecting approximately 5 million adults in the United States, with no curative treatment other than liver transplantation. Despite decades of research, therapeutic development has been hindered by the limited translational relevance of preclinical models, which fail to fully replicate key human MASH phenotypes—such as hepatocyte senescence and ballooning, bridging fibrosis, and the presence of TREM2+ fibrotic scar-associated macrophages. To address these limitations, we developed a novel 3D triple co-culture model using hepatic organoids derived from MASH patient liver tissue. This system incorporates hepatocyte-like cells, primary human hepatic stellate cells, and peripheral blood-derived macrophages. It preserves the disease-specific epigenetic landscape of MASH liver parenchyma and successfully recapitulates hallmark features of MASH pathology, including hepatocyte senescence and ballooning, bridging fibrosis, and TREM2+ macrophages accumulating on activated myofibroblasts—features poorly represented in conventional models. To enable cell type specific targeted intervention, we chose to engineer lipid nanoparticles (LNPs) for rapid genome editing in activated myofibroblasts, achieving >90% nuclear YAP1 knockdown within 48 hours when using YAP siRNA payloads. This led to significant myofibroblast senescence, as shown by upregulation of the senescence marker p21. This same LNP did not target hepatocytes nor macrophages within our model. Future work explores inducing myofibroblast death via specifically targeting senescent myofibroblasts. Ultimately, our MASH patient liver derived 3D fibrosis model combined with LNP-based genome editing offers a promising translational tool to both identify novel genetic targets and enable cell-type specific therapeutic targeting.

  Publisher

Recent grants

• Engineering Smart Protein Coronas to Advance Theraputic mRNA Delivery

  NIH · $66k · 2019–2021

• Engineering Smart Protein Coronas to Advance Theraputic mRNA Delivery

  NIH · $61k · 2019–2021

Frequent coauthors

• Emily S. Day

  Center for Cancer Research

  12 shared

• Kathryn A. Whitehead

  Carnegie Mellon University

  9 shared

• Namit Chaudhary

  Carnegie Mellon University

  7 shared

• Drew Weissman

  University of Pennsylvania

  5 shared

• George K. Gittes

  University of Pittsburgh Medical Center

  4 shared

• Mariah L. Arral

  Carnegie Mellon University

  4 shared

• Rachel Riley

  Rowan University

  4 shared

• Katherine C. Fein

  Carnegie Mellon University

  4 shared

Education

• Doctor of Philosophy, Biomedical Engineering

  University of Delaware

  2018

• Bachelor of Science, Biomedical Engineering

  Rutgers University

  2013