About

Ester J. Kwon is an Associate Professor of Bioengineering at the University of California San Diego. She earned her B.S. in Bioengineering and B.A. in Molecular & Cell Biology at UC Berkeley, followed by a Ph.D. in Bioengineering at the University of Washington under the mentorship of Suzie H. Pun. During her doctoral studies, she engineered polymeric nanoparticles grafted with peptides to impart biological function for delivering therapeutic nucleic acids into the central nervous system. Dr. Kwon completed her postdoctoral research in the laboratory of Sangeeta N. Bhatia at the Massachusetts Institute of Technology, where she developed various nanomaterial scaffolds for applications in cancer, bacterial infections, and traumatic brain injury. Her laboratory at UCSD focuses on engineering nanoscale tools, diagnostics, and treatments targeting diseases of the central nervous system. Dr. Kwon is committed to fostering an inclusive research environment through individualized mentorship and outreach to young scientists. She has been recognized with several prestigious awards, including the NIH Ruth L. Kirschstein National Research Service Awards, the 2018 NIH Director’s New Innovator Award, a 2021 NSF CAREER Award, and the Joan and Irwin Jacobs-Kavli Foundation Chancellor’s Endowed Faculty Fellowship in Brain and Mind.

Research topics

• Computer Science
• Medicine
• Biology
• Chemistry
• Computer Security
• Materials science
• Neuroscience
• Cell biology
• Biomedical engineering
• Nanotechnology

Selected publications

• Impact of Conjugation Chemistry on the Pharmacokinetics of Peptide–Polymer Conjugates in a Model of Traumatic Brain Injury

  Bioconjugate Chemistry · 2025-06-27 · 2 citations

  articleOpen accessSenior authorCorresponding

  Traumatic brain injury (TBI) remains a leading cause of long-term disability and mortality; however, there are no effective therapies to mitigate secondary injury and long-term neurological impairments. After the initial mechanical insult, there is a secondary injury that leads to neuroinflammation and blood-brain barrier (BBB) disruption, both of which are linked to changes in the extracellular matrix (ECM). A short peptide sequence, CAQK (Cys-Ala-Gln-Lys), targets upregulated ECM proteoglycans after TBI and has exhibited therapeutic properties in preclinical TBI studies. However, like many peptides, CAQK has poor pharmacokinetics, with rapid systemic clearance limiting its therapeutic potential. To overcome these limitations, we investigated a peptide-polymer conjugate using a poly(ethylene glycol) (PEG) scaffold to improve the peptide pharmacokinetics of CAQK. We synthesized materials using two conjugation chemistries, maleimide-thiol Michael-type addition and dibenzocyclooctyne (DBCO)-azide strain-promoted azide-alkyne cycloaddition. The impact of linker selection on biodistribution and clearance was distinct. We first showed that conjugation of CAQK to PEG, irrespective of linkers, significantly extended the peptide's blood half-life by 90-fold and increased brain accumulation. In the analysis of off-target organs, we observed longer retention of DBCO conjugates in the liver, kidney, and spleen compared to maleimide conjugates. Given the high incidence of TBI in populations such as military personnel and athletes, we explored whether our long-circulating material could be given as a prophylaxis. We demonstrated the accumulation of 4.5%ID/g CAQK in the injured brain when the conjugate was delivered prophylactically 24 h before injury. Our work underscores the advantage of long-circulating peptide-polymer conjugates in the context of TBI and the impact of conjugation chemistry on pharmacokinetics.

  PublisherDOI

• Enhanced neuronal transfection in the injured brain following systemic delivery of peptide-targeted lipid nanoparticles

  Molecular Therapy — Nucleic Acids · 2025-12-29

  articleOpen accessSenior author

  The consequence of traumatic brain injury (TBI) is significant loss of nervous tissue that leads to long-term neurological deficits. Nucleic acid payloads offer potential treatments that can address the complex pathophysiology that unfolds after injury. TBI causes a transient disruption of the blood-brain barrier, allowing access of systemically administered nanoparticles to the affected nervous tissue. In this work, we evaluated the dosing window post-injury in which lipid nanoparticles (LNPs) carrying mRNA can access and transfect the injured brain after systemic administration and identified 24 h post-injury as a delivery time that achieves both LNP access and transfection activity. We observed that transfected cell types were majorly astrocytes and endothelial cells with no appreciable transfection of neurons. To increase neuronal transfection, we functionalized LNPs with the peptide RVG and were able to increase the proportion of neurons transfected 6.4-fold over untargeted LNPs. These results identify timelines in which LNPs can access the injured brain parenchyma to mediate gene expression and strategies to achieve neuron-specific gene delivery.

  PublisherDOI

• Formulation methods for peptide-modified lipid nanoparticles

  Journal of Controlled Release · 2025-07-15 · 9 citations

  articleSenior authorCorresponding
  PublisherDOI

• Large-scale evaluation of the ability of RNA-binding proteins to activate exon inclusion

  Nature Biotechnology · 2024-01-02 · 33 citations

  articleOpen access

  RNA-binding proteins (RBPs) modulate alternative splicing outcomes to determine isoform expression and cellular survival. To identify RBPs that directly drive alternative exon inclusion, we developed tethered function luciferase-based splicing reporters that provide rapid, scalable and robust readouts of exon inclusion changes and used these to evaluate 718 human RBPs. We performed enhanced cross-linking immunoprecipitation, RNA sequencing and affinity purification-mass spectrometry to investigate a subset of candidates with no prior association with splicing. Integrative analysis of these assays indicates surprising roles for TRNAU1AP, SCAF8 and RTCA in the modulation of hundreds of endogenous splicing events. We also leveraged our tethering assays and top candidates to identify potent and compact exon inclusion activation domains for splicing modulation applications. Using these identified domains, we engineered programmable fusion proteins that outperform current artificial splicing factors at manipulating inclusion of reporter and endogenous exons. This tethering approach characterizes the ability of RBPs to induce exon inclusion and yields new molecular parts for programmable splicing control.

  PublisherOA PDFDOI

• MODELING TRAUMATIC BRAIN INJURY (TBI)–INDUCED NEURODEGENERATION USING HIPSC-CORTICAL ORGANOIDS

  Innovation in Aging · 2024-12-01

  articleOpen access

  Abstract Traumatic Brain Injury (TBI) is a serious injury that affects millions of people worldwide and has significant effects on neural pathways in the brain, making it a risk factor for neurodegenerative diseases. Most research that examines the link between TBI and neurodegeneration uses rodent models, however they do not fully recapitulate disease pathology and cannot capture human specific features including the effect of genetic variations. Human induced pluripotent stem cells (hiPSC)-derived cortical organoids have become the gold standard to model neurological disorders. They recapitulate certain aspects of physiological and neural pathways of the human brain and are easily reproducible, making them a better model. To understand the effects of TBI-induced neurodegeneration and explore potential treatment therapies, we model TBI in cortical hiPSC organoids through inducing mechanical injury. We assess AD-related morphological, biochemical, and functional downstream effects with a battery of assays. Among them, we measure the impact on neuronal activity using fluorescent Ca2+ indicators to measure Ca flux at a single-cell level post injury. Together, these assays will help us establish a human-based system to model in vitro TBI-induced neurodegeneration. We hope it can help contribute to evaluate specific therapies and diagnostic tools to stop progression of neurodegeneration after mechanical injury.

  PublisherOA PDFDOI

• Spatial Measurement and Inhibition of Calpain Activity in Traumatic Brain Injury with an Activity-Based Nanotheranostic Platform

  ACS Nano · 2024-09-05 · 7 citations

  articleOpen accessSenior authorCorresponding

  Traumatic brain injury (TBI) is a major public health concern that can result in long-term neurological impairments. Calpain is a calcium-dependent cysteine protease that is activated within minutes after TBI, and sustained calpain activation is known to contribute to neurodegeneration and blood-brain barrier dysregulation. Based on its role in disease progression, calpain inhibition has been identified as a promising therapeutic target. Efforts to develop therapeutics for calpain inhibition would benefit from the ability to measure calpain activity with spatial precision within the injured tissue. In this work, we designed an activity-based nanotheranostic (ABNT) that can both sense and inhibit calpain activity in TBI. To sense calpain activity, we incorporated a peptide substrate of calpain flanked by a fluorophore/quencher pair. To inhibit calpain activity, we incorporated calpastatin peptide, an endogenous inhibitor of calpain. Both sensor and inhibitor peptides were scaffolded onto a polymeric nanoscaffold to create our ABNT. We show that in the presence of recombinant calpain, our ABNT construct is able to sense and inhibit calpain activity. In a mouse model of TBI, systemically administered ABNT can access perilesional brain tissue through passive accumulation and inhibit calpain activity in the cortex and hippocampus. In an analysis of cellular calpain activity, we observe the ABNT-mediated inhibition of calpain activity in neurons, endothelial cells, and microglia of the cortex. In a comparison of neuronal calpain activity by brain structure, we observe greater ABNT-mediated inhibition of calpain activity in cortical neurons compared to that in hippocampal neurons. Furthermore, we found that apoptosis was dependent on both calpain inhibition and brain structure. We present a theranostic platform that can be used to understand the regional and cell-specific therapeutic inhibition of calpain activity to help inform drug design for TBI.

  PublisherDOI

• Author Correction: Large-scale evaluation of the ability of RNA-binding proteins to activate exon inclusion

  Nature Biotechnology · 2024-02-28

  erratumOpen access
  PublisherOA PDFDOI

• Mechanobiological Modulation of <i>In Vitro</i> Astrocyte Reactivity Using Variable Gel Stiffness

  ACS Biomaterials Science & Engineering · 2024-06-13 · 17 citations

  articleOpen access

  After traumatic brain injury, the brain extracellular matrix undergoes structural rearrangement due to changes in matrix composition, activation of proteases, and deposition of chondroitin sulfate proteoglycans by reactive astrocytes to produce the glial scar. These changes lead to a softening of the tissue, where the stiffness of the contusion “core” and peripheral “pericontusional” regions becomes softer than that of healthy tissue. Pioneering mechanotransduction studies have shown that soft substrates upregulate intermediate filament proteins in reactive astrocytes; however, many other aspects of astrocyte biology remain unclear. Here, we developed a platform for the culture of cortical astrocytes using polyacrylamide (PA) gels of varying stiffness (measured in Pascal; Pa) to mimic injury-related regions in order to investigate the effects of tissue stiffness on astrocyte reactivity and morphology. Our results show that substrate stiffness influences astrocyte phenotype; soft 300 Pa substrates led to increased GFAP immunoreactivity, proliferation, and complexity of processes. Intermediate 800 Pa substrates increased Aggrecan+, Brevican+, and Neurocan+ astrocytes. The stiffest 1 kPa substrates led to astrocytes with basal morphologies, similar to a physiological state. These results advance our understanding of astrocyte mechanotransduction processes and provide evidence of how substrates with engineered stiffness can mimic the injury microenvironment.

  PublisherOA PDFDOI

• PEGylated Multimeric RNA Nanoparticles for siRNA Delivery in Traumatic Brain Injury

  Small · 2024-11-05 · 9 citations

  articleOpen accessSenior authorCorresponding

  Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long-term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub-100 nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT-based RNA particles, in this method, sub-100 nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG-RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half-life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF-α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub-100 nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI.

  PublisherOA PDFDOI

• Robust genome and cell engineering via in vitro and in situ circularized RNAs

  Nature Biomedical Engineering · 2024-08-26 · 21 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• CAREER: An engineered nanosensor to measure in vivo protease activity in traumatic brain injury

  NSF · $500k · 2021–2027

• Peptide-mediated delivery of siRNA for treatment of ovarian cancer

  NIH · $138k · 2014–2017

• NIH Grant F31NS064805

  NIH · $41k · 2011

• Nanoscale Biomaterials for Targeted Repair in Traumatic Brain Injury

  NIH · $2.4M · 2018–2023

Frequent coauthors

• Sangeeta N. Bhatia

  89 shared

• Erkki Ruoslahti

  Discovery Institute

  30 shared

• Rebecca M. Kandell

  University of California, San Diego

  21 shared

• Jinmyoung Joo

  Ulsan National Institute of Science and Technology

  20 shared

• Justin H. Lo

  Vanderbilt University

  20 shared

• Matthew Skalak

  Detroit Medical Center

  17 shared

• William C. Hahn

  Dana-Farber Cancer Institute

  16 shared

• Gary B. Braun

  16 shared

Labs

• Kwon LabPI

  Engineers nanoscale tools, diagnostics, and treatments for diseases of the central nervous system.

Education

• Postdoc., Health Sciences & Technology

  Massachusetts Institute of Technology

  2017

• Ph.D., Bioengineering

  University of Washington

  2010

• B.S. with honors, Bioengineering

  University of California Berkeley

  2004

• B.A. with honors, Molecular and Cell Biology

  University of California Berkeley

  2004

Awards & honors

• Joan and Irwin Jacobs-Kavli Foundation Chancellor's Endowed…