Hybrid ionizable polymer-lipid mRNA delivery systems for intratumoral immunotherapy

01 November 2020 → 31 October 2024
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Nanochemistry
  • Medical and health sciences
    • Biopharmaceutics
    • Applied immunology
mRNA immunotherapy nanotechnology
Project description

Despite the clinical success, a large fraction of patients remains unresponsive to immune checkpoint inhibitors. A growing body of evidence indicates that therapeutic unresponsiveness correlates with a lack of CD8+ T cells infiltration in the tumor microenvironment (TME). As the latter depends on prior innate immune activation and recruitment of dendritic cells, a window of opportunity emerges to re-engineer the TME from a so-called immunologically `cold` state into a `hot` state. We will develop a strategy to induce necroptosis in the TME through mRNA-mediated expression of the protein mixed lineage kinase domain-like protein (MLKL). By stimulating cancer cell death and recruitment and activation of dendritic cells, MLKL can turn a tumor into its own vaccine and to evoke systemic anti-tumor immune responses through a local treatment. To promote specificity of MLKL-encoding mRNA uptake by cancer cells upon local administration into the tumor, we propose an innovative nanoparticle formulation that stably entraps mRNA and binds to over-expressed sialic acid motifs on the cancer cells surface, while avoiding systemic dissemination of the mRNA. We furthermore design our formulation to release intact mRNA into the cytoplasm of the cells. Relying on a series of in vitro and in vivo mouse models, we aim to gain a proof-of-concept that our mRNA delivery systems hold promise to safe but potently induce tumor-specific immunity capable of suppressing metastatic growth.