Hemoglobin's α‐Helix‐to‐β‐Sheet Transition Enables Targeted mRNA Delivery to the Lung

ABSTRACT Effective treatment of pulmonary diseases remains constrained by the scarcity of delivery systems capable of selective tissue targeting. Herein, we report a lung‐targeting platform created through the structural repurposing of hemoglobin (Hb). Acidic heating enables a conformational shift of Hb from α‐helix to β‐sheet, leading to its self‐assembly into fibrils (HbFs). Unexpectedly, intravenously injected HbFs exhibit rapid and specific accumulation in the lungs. Cryo‐electron microscopy (cryo‐EM) structure determination revealed a fibril surface rich in positively charged residues, which facilitates two key functions: selective binding to circulating platelets via a hitchhiking mechanism for lung targeting, and efficient electrostatic complexation with mRNA. In a therapeutic application, HbFs loaded with mRNA encoding an interleukin‐11 single‐chain fragment variable (IL‐11 scFv) were administered in a murine model of bleomycin‐induced pulmonary fibrosis. The formulation achieved lung‐specific delivery with predominant uptake by pulmonary fibroblasts, enabling sustained local IL‐11 scFv expression. Consequently, treatment significantly suppressed fibroblast activation and migration, attenuated collagen deposition, restored lung function. This work establishes HbFs as a novel protein‑based vehicle for targeted mRNA delivery, leveraging natural cellular trafficking pathways to enable localized therapy for lung disorders.