Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation

Liam M Casey; Sandeep Kakade; Joseph T Decker; Justin A Rose; Kyle Deans; Lonnie D Shea; Ryan M Pearson

doi:10.1016/j.biomaterials.2019.119333

Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation

Biomaterials. 2019 Oct:218:119333. doi: 10.1016/j.biomaterials.2019.119333. Epub 2019 Jul 4.

Authors

Liam M Casey¹, Sandeep Kakade², Joseph T Decker², Justin A Rose², Kyle Deans², Lonnie D Shea³, Ryan M Pearson⁴

Affiliations

¹ Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA.
² Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA.
³ Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA. Electronic address: ldshea@umich.edu.
⁴ Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA; Department of Pharmaceutical Sciences, University of Maryland, 20 N. Pine Street, Baltimore, MD, 21201, USA. Electronic address: rpearson@rx.umaryland.edu.

Abstract

Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) signaling, which activates numerous inflammatory pathways. The breadth of this inflammation has limited the efficacy of pharmacological interventions that target a single molecular pathway. Here, we developed cargo-less particles as a single-agent, multi-target platform to elicit broad anti-inflammatory action against innate immune cells challenged by multiple TLR agonists. The particles, prepared from poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), displayed potent molecular weight-, polymer composition-, and charge-dependent immunomodulatory properties, including downregulation of TLR-induced costimulatory molecule expression and cytokine secretion. Particles prepared using the anionic surfactant poly(ethylene-alt-maleic acid) (PEMA) significantly blunted the responses of antigen presenting cells to TLR4 (lipopolysaccharide) and TLR9 (CpG-ODN) agonists, demonstrating broad inhibitory activity to both extracellular and intracellular TLR ligands. Interestingly, particles prepared using poly(vinyl alcohol) (PVA), a neutrally-charged surfactant, only marginally inhibited inflammatory cytokine secretions. The biochemical pathways modulated by particles were investigated using TRanscriptional Activity CEll aRrays (TRACER), which implicated IRF1, STAT1, and AP-1 in the mechanism of action for PLA-PEMA particles. Using an LPS-induced endotoxemia mouse model, administration of PLA-PEMA particles prior to or following a lethal challenge resulted in significantly improved mean survival. Cargo-less particles affect multiple biological pathways involved in the development of inflammatory responses by innate immune cells and represent a potentially promising therapeutic strategy to treat severe inflammation.

Keywords: Cellular reprogramming; Endotoxemia; Immunomodulation; Inflammation; Nanoparticles; Sepsis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endotoxemia / immunology
Endotoxemia / metabolism
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Immunity, Innate / genetics
Immunity, Innate / physiology*
Inflammation / immunology
Inflammation / metabolism
Mice
Mice, Inbred C57BL
Nanoparticles / chemistry*
Polyesters / chemistry
Polylactic Acid-Polyglycolic Acid Copolymer / chemistry
RAW 264.7 Cells
Sepsis / immunology
Sepsis / metabolism
Toll-Like Receptors / metabolism*

Substances

Polyesters
Toll-Like Receptors
Polylactic Acid-Polyglycolic Acid Copolymer
poly(lactide)

Abstract

Publication types

MeSH terms

Substances

Grants and funding