Cationic Nanoplastics Assemble Lipid A Coronas That Alter TLR4 Signaling and Impair Endotoxin Tolerance

Micro- and nanoplastics are pervasive, yet their capacity to modify host recognition of microbial ligands remains incompletely understood. Here we show that amine-functionalized polystyrene nanoplastics (PS-NH₂) act as a chemically defined cationic endmember that sequesters lipid A, assembling compact lipopolysaccharide (LPS) coronas that reduce productive engagement of the TLR4-MD-2 complex. Biophysical readouts (DLS, zeta potential, TEM, and UV-vis) and all-atom molecular dynamics support tight coronas driven by cooperative hydrophobic insertion and hydrogen bonding. Functionally, coexposure attenuates MyD88-NF-kB and TRIF-IRF3 signaling in primary human monocytes and in vivo suppresses acute cytokine output and impairs the establishment of endotoxin tolerance during conditioning. In proof-of-principle in vivo conditioning models, PS-NH₂ counteracts LPS-mediated protective effects in type-1 diabetes and house-dust-mite allergy settings. These effects are strongest for the fresh, strongly cationic particle state, are attenuated by UV weathering and gastrointestinal protein-corona formation, and vary with LPS source, particle size, and particle-to-LPS ratio. Together, these findings identify a corona-mediated route by which a defined nanoplastic surface state can alter microbial recognition under controlled coexposure conditions.