Engineered Lactoferrin Nanoparticle Coronas as a Tunable Platform for Immunomodulation and Antibacterial Function

Lactoferrin (Lf) is a multifunctional endogenous glycoprotein with well-established antimicrobial and immunomodulatory activities. In this work, we report a modular nanoparticle (NP) platform in which Lf is engineered as a multilayered protein corona onto immunomodulatory poly(lactic-co-glycolic acid) NPs (PLGA@Lf). By integrating the intrinsic anti-inflammatory properties of PLGA NPs with the diverse bioactivities of Lf, this hybrid corona design enables concurrent immune activation and suppression while enhancing antibacterial functionality. We demonstrate that Lf stably adsorbs onto PLGA NPs in a concentration-dependent manner, altering particle size and zeta potential consistent with multilayered corona formation. PLGA@Lf was shown to stimulate innate immune cells, enhancing Escherichia coli bioparticle phagocytosis, while simultaneously reducing pro-inflammatory cytokine levels in lipopolysaccharide (LPS)-challenged macrophages. Further antimicrobial activity studies demonstrated robust inhibition of bioluminescent E. coli activity in vitro. Lastly, in an in vivo therapeutic LPS-induced endotoxemia model, PLGA@Lf significantly reduced plasma levels of TNF-α compared to uncoated controls, highlighting their enhanced anti-inflammatory properties. Collectively, these results establish PLGA@Lf NPs as a dual-function nanomaterial platform that efficiently balances both immune stimulation and suppression responses, offering a promising strategy for managing infectious and inflammatory diseases.