N‐Acetylcysteine–Mediated Surface Remodeling of Inhaled mRNA Lipid Nanoparticles Enables Coordinated Mucosal and Systemic Antitumor Immunity

Inhaled messenger RNA (mRNA) delivery is constrained by aerosolization-induced stress and airway barriers that limit post-deposition transport and immune activation. Here, we report an N-acetylcysteine (NAC)-enabled strategy that dynamically remodels inhaled mRNA lipid nanoparticles (LNP) after airway deposition. The LNPs are stabilized through electrostatic repulsions during nebulization by a negatively charged, disulfide-linked peptide-lipid conjugate on the LNP surface. Following deposition, NAC mediates thiol-disulfide exchange to cleave the peptide-lipid linkage, removing the anionic peptide and restoring cellular uptake while preserving aerosol stability. Concurrently, NAC reduces mucus density as a mucolytic, enhancing LNP penetration and trans-epithelial transport. As a result, inhaled mRNA-LNP yields robust pulmonary mRNA expression and enables mRNA expression in extrapulmonary tissues. Immunologically, inhaled mRNA-LNPs elicit strong mucosal immune responses, while NAC-enabled delivery additionally activates systemic immune activation. In mouse tumor models, this strategy achieves complete eradication of distant tumors and confers durable protection against tumor rechallenge. These findings highlight the potential of dynamic nanoparticle surface remodeling to overcome barriers in inhaled mRNA delivery.