# Characterizing DC-specific mechanisms of LNP immunogenicity to enhance LNP-based anti-tumor therapies

> **NIH NIH F30** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $42,724

## Abstract

PROJECT SUMMARY
In the first 6 months after COVID-19 vaccine approval, 3.4 billion doses were administered globally, potentially
saving 7.2 million lives. Lipid nanoparticle (LNP)-mRNA based COVID-19 vaccines have been able to induce
both a strong T cell- and antibody-mediated responses against SARS-CoV-2 by triggering myeloid antigen
presenting cells (APCs) such as dendritic cells (DCs), demonstrating the efficacy of LNP-mRNA technology to
modulate the immune system. Partly due to the success of COVID-19 vaccines, there has been a renewed
attention in engineering novel LNP formulations to better modulate the myeloid APC compartment by 1) either
fine-tuning the adjuvanticity of the LNP lipid formulation or 2) improving in vivo targeting efficiency of LNPs
towards myeloid APCs. Although the advancements in LNP lipid chemistry enrich our arsenal of LNP
formulations suited to modulate the immune system, there hasn't been a corresponding detailed understanding
of the molecular and cellular changes induced upon the uptake of LNPs in specific cell types and tissues. In
fact, attempts to elucidate the innate mechanisms of LNP immunogenicity have often led to conflicting
conclusions and have in turn suggested that the mechanisms of LNP immunogenicity are rather LNP
formulation-dependent. The lack of consensus on the innate mechanisms of LNP immunogenicity further
highlight that the immunogenicity of each LNP is a complex function of a) its lipid formulation and the nature of
its payload, b) the pattern recognition receptor (PRR) profile unique to each immune subset, c) LNP targeting
efficiency in each cell type and d) cell, tissue and disease context of LNP treatment. Without the parallel efforts
to gain mechanistic understanding of immunogenicity of each LNP formulation, it remains difficult to rationally
select LNP formulations that are tailored to a particular disease context, including cancer. In using LNPs as a
cancer immunotherapeutic, my central hypothesis states that LNP lipid formulations that drive up their
immunogenicity combined with an engineering strategy to increase specific targeting of DCs in vivo can
synergize with immunostimulatory payloads (i.e. IL-12) to reprogram DC cell states and enhance anti-tumor
immunity. In Aim 1, I will characterize the changes in DC phenotype, function and transcriptional profile upon
uptake of DC-targeted LNPs in both steady state and tumoral contexts using DC-T cell co-cultures, bulk and
scRNA-seq of sorted LNP transfected DCs. In Aim 2, I will engineer Clec9a targeted bi-specific antibodies to
improve LNP transfection of DCs in vivo. The outcome of this project is both a mechanistic understanding of
the interplay between LNPs and DCs that occurs upon LNP uptake and a novel bi-specific antibody-based
strategy to increase DC targeting in vivo.

## Key facts

- **NIH application ID:** 10994716
- **Project number:** 1F30CA287638-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Chang Yoon Moon
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,724
- **Award type:** 1
- **Project period:** 2024-07-15 → 2027-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994716

## Citation

> US National Institutes of Health, RePORTER application 10994716, Characterizing DC-specific mechanisms of LNP immunogenicity to enhance LNP-based anti-tumor therapies (1F30CA287638-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10994716. Licensed CC0.

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