Human Gut Bacteria and Lipidic Nanoparticles: Particle Composition Predicts Structural Transformation and Bacterial Biocompatibility

ABSTRACT Modern nanomedicine assumes sterile test conditions, but target sites such as the skin and gut are colonised by diverse bacterial communities. How lipidic nanoparticles (LNPs) behave in these microbially rich environments remains unknown. Here, we examine the interactions between five LNP formulations and 21 gut bacterial species frequently associated with the human microbiome, independently assessing effects on bacterial growth. LNP nanostructure was resolved using small‐angle X‐ray scattering (SAXS) and microbial growth assessed using spot assays. Our results indicate that monoolein (MO) LNPs underwent structural reorganisation following exposure to ∼75% of species tested, whereas phytantriol (PYT) and phospholipid LNPs were largely unchanged. PYT LNPs broadly inhibited bacterial growth at 0.25 mg/mL, whereas MO LNPs showed broader inhibition only at 25 mg/mL, and phospholipid liposomes did not inhibit growth at any concentration tested. Together, these findings indicate that LNP composition—rather than initial internal nanostructure alone—is the primary predictor of both susceptibility to structural reorganisation and bacterial biocompatibility. These insights can guide LNP design for oral and suppository applications and suggest that the human microbiome has clear implications for nanomaterial development across health and disease.