The gut microbiota regulates the protein corona formation, biodistribution, and cellular uptake of lipid nanoparticles

Nanomedicines promise to transform oncology by improving pharmacokinetics, enhancing tumor targeting, and reducing systemic toxicities relative to conventional chemotherapies. However, clinical outcomes remain inconsistent, with marked inter-patient variability in biodistribution and therapeutic response. This variability is thought to arise from heterogeneity in "bio-nano" interactions, yet the upstream drivers of these interactions are poorly defined. We propose that the gut microbiota is a clinically relevant regulator of nanomedicine behavior, given its established influence on host immunity, metabolism, and proteome composition - all key determinants of bio-nano interactions. To test this, rats underwent a 14-day microbiota modulation using a prebiotic, broad-spectrum antibiotics, or control treatment. PEGylated liposomes were then intravenously administered to assess the impact of microbiota composition on (i) protein corona formation, (ii) nanoparticle biodistribution, and (iii) in vitro anti-cancer efficacy of doxorubicin-loaded liposomes following exposure to plasma from each group. Microbiota modulation produced distinct protein coronas, characterized by increased protein adsorption and unique proteomic profiles enriched in complement factors, apolipoproteins, and immunoglobulins. These corona differences were associated with altered biodistribution profiles, affecting both the magnitude and organ-level partitioning of nanoparticle-associated signal. Antibiotic treatment increased total systemic signal consistent with altered retention and/or clearance, whereas prebiotic supplementation was associated with reduced overall signal and decreased proportional partitioning into mononuclear phagocyte system organs, with a corresponding shift in distribution balance toward peripheral tissues including the heart, kidney, and brain. Notably, the prebiotic-derived corona markedly enhanced liposomal uptake and cytotoxicity in A549 and ES-2 cancer cells, linking protein adsorption and corona composition with bio-nano cellular interactions. Collectively, these findings provide experimental evidence that microbiota modulation influences nanoparticle behavior by altering bio-nano interactions, revealing an emerging "gut-nano axis" as a potentially controllable source of nanomedicine variability.