Particle Shape Modulates the Function of Adoptive Macrophage Transfers.

Abstract

Adoptive cell transfers (ACTs) constitute an emerging platform for improving the systemic delivery of nano- and microparticle systems. Macrophages (Mφ) are an attractive cell type for particle-carrying ACTs because their attachment, phagocytosis, and chemotaxis can improve pharmacokinetics and reduce off-target effects. However, little is known about how macrophage transport and function change when carrying particles of different shapes, or whether these changes can be leveraged for improving ACTs. This work investigates macrophage interactions with biodegradable spherical and discoidal particles to promote or suppress phagocytosis, respectively. Adoptively transferred macrophages with internalized spheres (Mφ-S) or surface-bound discs (Mφ-D) possess enhanced targeted delivery to solid tumors compared to conventional free microparticle administration by 5.2-fold and exhibit distinct phenotypic profiles within the cold B16-F10 tumor microenvironment. Moreover, phenotypic changes are evaluated upon particle association by profiling the transcriptional, chromatin accessibility, and protein state. Mφ-S complexes adopt epigenetic changes and key biomarkers associated with a proinflammatory phenotype. In Mφ-D complexes, a diverse chromatin and protein landscape with simultaneous upregulation of both pro- and anti-inflammatory biomarkers is observed, suggesting functional flexibility is observed. These findings suggest particle shape can be used as a design parameter to influence the function of adoptive macrophage transfers without compromising their delivery performance.