Experimental evidence and consequences of biomolecular corona formation on inhaled mRNA lipid nanoparticles

Abstract Inhalable messenger RNA (mRNA) therapeutics are moving pulmonary drug delivery from local deposition of small molecules toward transient, programmable expression of antigens, secreted proteins, antibodies, gene-editing enzymes and replacement proteins directly within the respiratory tract. Their translation, however, cannot be extrapolated from intramuscular or intravenous lipid nanoparticle (LNP) experience. Inhaled mRNA nanoparticles need to remain colloidally and structurally stable during aerosol generation, deposit in appropriate lung regions, traverse mucus or surfactant-rich hypophase fluids, evade excessive mucociliary and macrophage clearance, and finally promote endosomal escape in epithelial, myeloid or antigen-presenting cells. At each stage, the manufactured particle acquires a dynamic biological identity created through adsorption and exchange of proteins, lipids, mucins, complement components and surfactant collectins. This narrative review critically synthesizes experimental evidence on biomolecular corona formation around inhaled mRNA nanoparticles and closely related pulmonary nanocarriers, thereby addressing a current gap in the literature. Whereas existing reviews have largely focused on inhaled nanomaterials in general or on systemically administered lipid nanoparticles, none has specifically examined the biocorona of inhaled mRNA delivery systems. We distinguish respiratory coronas from plasma coronas, integrate proteomic, lipidomic and imaging studies of respiratory tract lining fluid and pulmonary surfactant, and examine how corona composition can modulate mucus penetration, macrophage recognition, epithelial access, cellular uptake, endosomal trafficking, inflammation and immunogenicity. We further evaluate how nebulization and aerosolization alter particle surfaces and may subsequently influence corona formation, and discuss device-formulation co-design strategies, including PEG-lipid tuning and charge-assisted stabilization. Finally, we propose experimental readouts and translational design principles for corona-aware inhaled mRNA therapeutics, emphasizing that pulmonary efficacy should be evaluated through a comprehensive framework that includes biomolecular corona characterization.