Advancing NANOmedicines to rewire tumoral MYeloid cells for next-generation cancer immunotherapies

Persistent inflammation during tumorigenesis drives myelopoiesis. Consequently, monocytes and granulocytes/neutrophils infiltrate the tumor microenvironment (TME) and differentiate into tumor-associated macrophages or myeloid-derived suppressor cells, creating an immune-suppressive microenvironment that hampers cytotoxic T cell function and limits immune checkpoint inhibitor (ICI) efficacy. ‘Reprogramming’ myeloid cells to adopt pro-inflammatory phenotypes is promising to restore immune function and enhance ICI responses. Lipid nanoparticles (LNPs) have emerged as a delivery platform for nucleic acids, as demonstrated by the mRNA-LNP COVID vaccines. Pioneering studies revealed that myeloid cells are robustly recruited to the vaccine injection site where they internalize mRNA-LNPs, leading to mRNA expression in monocytes. While nanoparticle (NP) transport into inflamed tissues and tumors has been attributed to ‘enhanced permeation/retention’ of the NPs, my recent findings, in an inflamed arthritis model, highlight a critical role of circulating myeloid cells in the active transport of intravenously injected LNPs. Therefore, I hypothesize that mRNA-LNPs can transfect tumor-infiltrating myeloid cells reversing immune-suppression. My-NANO will study interactions between myeloid cells and lipid-based NPs through the following objectives: (1) elucidating the role of myeloid cells in the transport of lipid-based NPs to tumors (WP1), (2) investigating how mRNA-LNPs influence innate immune responses/phenotype switches in myeloid cells (WP2) and (3) optimizing mRNA-LNP design for efficient/selective mRNA expression in myeloid cells (WP3). Based on this knowledge My-NANO will design mRNA-LNPs to restore the phagocytic function of myeloid cells by knocking out SIRP-1α or by generating CAR-macrophages to enhance tumor responses to ICIs (WP4). By employing state-of-the-art methodologies, My-NANO hopes to advance mRNA-LNPs as ‘myeloid cell therapeutics’ for cancer immunotherapy.