Distinct Inflammatory Programs Underlie the Intramuscular Lipid Nanoparticle Response

Nov 20, 2024ACS nano

Different Inflammatory Responses Behind Muscle Reactions to Lipid Nanoparticles

AI simplified

mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Intramuscular injection of Class A empty lipid nanoparticles (eLNPs) induces robust neutrophil infiltration into muscle within 2 hours.

Two classes of inflammatory gene expression programs were identified: inflammatory (Class A) and noninflammatory (Class B).
Class A eLNPs lead to activation of myeloid cells and subsequent expression of inflammatory chemokines within muscle tissue by 24 hours.
Direct transfection of muscle-infiltrating myeloid cells and splenocytes occurs 24 hours after administration of mRNA/lipid nanoparticles.
Type II conventional dendritic cells (cDC2s) in the spleen are directly transfected and activated by Class A mRNA/lipid nanoparticles.
The findings suggest that mRNA and lipid nanoparticles may work together to elicit a robust innate immune response necessary for effective vaccination.

AI simplified

Developments in mRNA/lipid nanoparticle (LNP) technology have advanced the fields of vaccinology and gene therapy, raising questions about immunogenicity. While some mRNA/LNPs generate an adjuvant-like environment in muscle tissue, other mRNA/LNPs are distinct in their capacity for multiple rounds of therapeutic delivery. We evaluate the adjuvancy of components of mRNA/LNPs by phenotyping cellular infiltrate at injection sites, tracking uptake by immune cells, and assessing the inflammatory state. Delivery of 9 common, but chemically distinct, LNPs to muscle revealed two classes of inflammatory gene expression programs: inflammatory (Class A) and noninflammatory (Class B). We find that intramuscular injection with Class A, but not Class B, empty LNPs (eLNPs) induce robust neutrophil infiltration into muscle within 2 h and a diverse myeloid population within 24 h. Single-cell RNA sequencing revealed SM-102-mediated expression of inflammatory chemokines by myeloid infiltrates within muscle 1 day after injection. Surprisingly, we found direct transfection of muscle infiltrating myeloid cells and splenocytes 24 h after intramuscular mRNA/LNP administration. Transfected myeloid cells within the muscle exhibit an activated phenotype 24 h after injection. Similarly, directly transfected splenic lymphocytes and dendritic cells (DCs) are differentially activated by Class A or Class B containing mRNA/LNP. Within the splenic DC compartment, type II conventional DCs (cDC2s) are directly transfected and activated by Class A mRNA/LNP. Together, we show that mRNA and LNPs work synergistically to provide the necessary innate immune stimuli required for effective vaccination. Importantly, this work provides a design framework for vaccines and therapeutics alike.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text ↗

Distinct Inflammatory Programs Underlie the Intramuscular Lipid Nanoparticle Response

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief