Date of Award

2026-08-01

Degree Name

Master of Science

Department

Biomedical Engineering

Advisor(s)

Wilson Poon

Abstract

Sepsis is a life-threatening condition caused by a dysregulated host response to infection and remains a leading cause of mortality worldwide. It is characterized by an initial hyperinflammatory phased followed by prolonged immunosuppression. Current treatments focus on eliminating the underlying infection or mitigating early inflammation, rather than correcting immune dysregulation. The liver acts as a key regulator of systemic inflammation, with Kupffer cells (resident liver macrophages) acting as major producers of pro-inflammatory cytokines. Lipid nanoparticles (LNPs) are a promising therapeutic delivery platform as they have a natural tropism to accumulate in the liver and interact with macrophages. Immunomodulatory bioactive lipids (IBLs) are lipid molecules that regulate immune signaling pathways. By incorporating IBLs into LNP formulations, we aim to develop cytokine adjusting lipid modulator (CALM) nanoparticles capable of modulating inflammatory responses to treat sepsis and other inflammatory diseases. To achieve this, we first generated a CALM-NP library containing diverse IBLs and evaluated their incorporation on nanoparticle physicochemical properties. Then, we screened the immunomodulatory activity of each CALM-NP formulation in lipopolysaccharide (LPS) stimulated RAW-Dual reporter macrophages by measuring NF-kB activation using a colorimetric readout assay, as well as quantifying inflammatory cytokine (IL-6 and TNF-α) production through ELISA. The top-performing CALM-NP formulations were further biologically characterized through cell uptake, cell viability, and reactive oxygen species (ROS) analyses. Through this screening framework, we successfully identified several novel CALM-NP formulations capable of reducing LPS-induced inflammatory response. The most promising candidates decreased NF-kB activation, reduced pro-inflammatory cytokine production and ROS generation, and showed no adverse effects on cell uptake or viability. Together, these findings demonstrate the potential of bioactive lipids to enhance the immunomodulatory properties of LNPs, and establish CALM-NPs as a promising therapeutic strategy for sepsis and potentially other inflammatory diseases.

Language

en

Provenance

Received from ProQuest

File Size

47 p.

File Format

application/pdf

Rights Holder

Jael Chavez Contreras

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