A backpack-based myeloid cell therapy for multiple sclerosis

Abstract

Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles (“backpacks”) for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on T H 1 and T H 17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype in vivo, demonstrating the utility of myeloid cells as a therapeutic modality and target.

ROS-responsive nanoparticle delivery of ferroptosis inhibitor prodrug to facilitate mesenchymal stem cell-mediated spinal cord injury repair

“…Recent reports indicate that a “cellular backpack” strategy is being used for the treatment of stroke, which conjugates drug-loaded micelles on the surface of MSCs. The results confirmed that packed MSCs showed excellent efficacy in cell migration, cell survival, and reduction of oxidative stress in the lesion area [ 74 , 75 ]. The nanodrug micelles conjugation strategies on the surface of MSCs have a crucial impact on vesicle release and further therapeutic efficacy.…”

Polymer Micropatches as Natural Killer Cell Engagers for Tumor Therapy

“…Here, we present a strategy to continuously stimulate NK cells that is scalable, is rapidly deployable, and can synergize with current priming methods in the clinic. Previously, our group reported the use of polymeric discoidal microparticles that attach to the cell surface and resist phagocytic internalization due to their geometry. − We utilized this discoidal shape as a basis for designing MACE, to create a modular platform that can be functionalized with surface antibodies or ligands targeting various receptors on the NK cell, thus allowing us to modulate cellular activation status. We designed MACE to target NK receptors of the natural cytotoxicity receptor (NCR) family, specifically NKp30 and NKp46, and deliver constant activating signals to the cell.…”

Polymer Micropatches as B-Cell Engagers

“…Previously, we demonstrated the ability of antibody-functionalized polymeric micropatches, a platform termed as Micropatches as Cell Engagers (MACE), to engage multiple cell surface receptors and induce robust signaling via receptor cross-linking . Due to the unique discoidal shape and high aspect ratio, these micropatches can resist cellular internalization and remain attached to the surface of many immune cells, including macrophages, , monocytes, natural killer (NK) cells, and neutrophils . Here, we further develop MACE to induce B-cell signaling via receptor multimerization, resulting in a potent and sustained activation of the cells (Figure ).…”