Micro- and nanoplastics remodel the autophagy-lysosomal axis and mitochondrial function in primary human monocytes

Background Micro- and nanoplastics (MNPs) are increasingly detected in human tissues, raising concerns regarding their potential impact on immune cell function. Monocytes are among the first immune cells to encounter and internalize these particles. However, the intracellular mechanisms triggered by MNPs exposure remain poorly understood. Methods Primary human monocytes were exposed to 25µg/mL of polystyrene (PS) MNPs ranging from 0.5 to 5 µm. Particle uptake and intracellular trafficking were investigated by transmission electron microscopy (TEM), while autophagy–lysosomal and mitochondrial responses were assessed by Western blotting, quantitative PCR, ultrastructural analyses, and metabolic flux measurements. Results Ultrastructural TEM analysis revealed that primary human monocytes internalize MNPs through phagocytosis, followed by phagosome maturation and fusion with lysosomes. At a molecular level, MNPs exposure is associated with marked remodeling of the autophagy–lysosomal system, characterized by increased lysosomal abundance, elevated LC3-II/I ratio, and accumulation of autophagy-related vesicular structures. Although p62 protein levels increased following exposure, no corresponding changes were observed at the transcriptional level for key autophagy-associated genes, suggesting predominantly post-transcriptional regulation of these pathways. MNPs exposure also altered mitochondrial organization, increasing mitochondrial number while reducing mitochondrial area. Consistently, expression of the mitophagy-related gene PINK1 increased, particularly following exposure to 1µm particles. Functional analyses demonstrated size-dependent mitochondrial dysfunction, with 0.5µm and 1µm particles reducing mitochondrial respiratory capacity, whereas 5µm particles exerted minimal effects. Conclusions To our knowledge, this study provides the first integrated, size-resolved characterization of MNPs uptake and intracellular responses in primary human monocytes, combining ultrastructural and biological evidence of phagocytic internalization, autophagy-lysosomal flux, mitochondrial homeostasis, and cellular bioenergetics within the same experimental framework. MNPs uptake was associated with concurrent alterations in the autophagy–lysosomal axis, mitochondrial homeostasis, and cellular metabolism. Our findings further provide evidence that exposure to MNPs at 25µg/mL affects key intracellular pathways involved in immune cell homeostasis. These results highlight a potential link between particle accumulation and cellular alterations, which may have implications for myeloid cell function and long-term health.