Amyloid-like albumin interface uncouples phagocytosis from inflammation through protein corona remodeling.

Abstract

Designing interfaces that promote macrophage uptake without provoking acute inflammatory activation remains a key challenge. Competitive protein adsorption at nanoparticle-biofluid interfaces dictates the functional immune profile of particles. Here, we addressed this challenge by constructing an amyloid-like human serum albumin (ALH) coating on Fe3O4 nanoparticles via disulfide-reduction-induced phase transition to generate a structurally robust protein interface. The ALH coating self-assembled into a displacement-resistant layer that resisted SDS desorption and serum exchange, whereas native HSA coatings were readily displaced. Quantitative proteomics revealed that ALH-coated particles selectively recruited lectin-pathway opsonins (FCN2, COLEC10/11), complement components (C3, C7) and the pentraxin MPTX, while HSA coatings predominantly favored DAMP alarmins (S100A8/A12), apolipoproteins and contact-system proteins. In the presence of serum, ALH-coated particles exhibited an approximately 7-fold higher fluorescence-normalized uptake index and more than threefold higher cell-associated iron than HSA-coated particles. Serum removal or FcγR blockade substantially reduced ALH uptake, implicating serum-derived FcγR-associated ligands. Despite markedly higher uptake, ALH-coated particles suppressed TNF-α and IL-1β secretion to 25-30% of the HSA group, accompanied by reduced NF-κB p65 nuclear translocation and a blunted, delayed proinflammatory transcriptional response. Extending these findings in vivo, ALH-Fe3O4 showed approximately two-fold greater macrophage-associated splenic iron accumulation at 4 h while maintaining lower splenic TNF-α and IL-1β immunoreactivity than HSA-Fe3O4. Collectively, these findings support β-sheet-enriched ALH coatings as a durable adsorption template that remodels corona composition and functionally decouples phagocytic uptake from proinflammatory signaling.

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