Distinct macrophage uptake of engineered and biological particles driven by host age and sex

Understanding how nano- and microparticles interact with biological systems is essential for advancing the biomedical applications of engineered materials. These interactions are governed not only by the physicochemical properties of the particles – such as size, shape, and surface chemistry – but also by host-specific physiological factors. However, how intrinsic host factors, particularly age and biological sex, affect interactions between immune cells and particles remains poorly understood. In this study, we systematically investigated how these intrinsic host variables influence the cellular uptake of polymeric particles by primary macrophages. Using a library of particles with controlled sizes (25, 250, and 3000 nm) and surface chemistries (unmodified, amine-, and carboxyl-functionalized), as well as with biological particles (bacteria and yeast), we compared uptake efficiencies in macrophages derived from male and female mice of various ages. We observed significant age- and sex-dependent differences in particle internalization. Transcriptomic profiling revealed differentially expressed genes related to receptor-mediated endocytosis and actin cytoskeleton remodeling, suggesting that molecular mechanisms underly these variations. Additionally, protein coronas were formed by incubating polymeric particles with autologous serum, revealing sex-dependent differences in corona composition and resulting macrophage recognition. Our findings highlight the critical interplay between engineered-material properties and host biological variability. Accordingly, this work provides key insights for the rational design of nanomaterials tailored to perform consistently across heterogeneous biological populations, thereby advancing the development of personalized nanomedicine and immunomodulatory materials. This study reveals how age and sex influence the macrophage uptake of particles, emphasizing the importance of host-dependent variability in designing consistent, personalized nanomedicines and advancing applications of immunomodulatory materials.