An Engineered Thio‐Amino Polymer Achieves Potent, Safe, and Broad Cell Type Delivery in the Lung Mapped by Spatial Transcriptomics

Efficient delivery of nucleic acids to the lung has the potential to impact future respiratory treatments. Current formulations exhibit significant limitations, including insufficient potency, single-cell delivery characterizations, efficacy demonstrations in disease models, and toxicology assessments. Here we describe polymer 81 (P81), which, when used with hypotonic solvents, is 34.1- to 77.8-fold more potent than previous polymers with various cargos for lung transfection by nebulized mRNA. Through the exploration of multiple routes of administration, P81 demonstrated a wide of range of cell-type delivery, including bronchial airway epithelial cells, tracheal basal stem cells, and 54% of all cells in the distal lung, assessed via single-cell spatial transcriptomics. Robust expression of mRNA-encoded antibodies in the lung by P81 enabled quantification of target protein and successful suppression of SARS-CoV-2 infection. The toxicology assessments of multiple doses of P81 polyplexes via nebulization in rodents were unremarkable. Overall, P81 represents a step forward for inhaled nucleic acid delivery to the respiratory tract, positioning itself as an efficient, safe, and translatable delivery formulation.