Delivering the blueprint: Advances and challenges in mRNA therapeutics for the respiratory system

The success of mRNA vaccines has established lipid nanoparticles (LNPs) as a clinically validated delivery platform, yet their application to pulmonary therapeutics presents formidable challenges. This review systematically summarizes the mechanisms, delivery methods, key challenges, safety considerations, and translational gaps associated with mRNA-LNP therapeutics for pulmonary disorders. It surveys LNP-mediated delivery to pulmonary cell populations, distinguishing readily accessible targets (such as alveolar type II cells, bronchial epithelia, and macrophages) from refractory cell types (including T cells and rare fibroblast subsets). The evolution of LNPs is traced through three generations: from initial hepatic-optimized carriers, to lung-tropic selective organ targeting (SORT) formulations, and onward to contemporary precision-engineered aerosol systems. These advances have enabled diverse mRNA-based therapeutic modalities, encompassing protein replacement, gene editing, cell reprogramming, and cancer immunotherapy, each of which is examined with emphasis on their distinct mechanisms of action and safety profiles. Lung cancer represents a particularly intractable therapeutic challenge. Stromal barriers and tumor-associated macrophages render most lung-selective LNPs ineffective in orthotopic models, necessitating development strategies decoupled from those for non-malignant indications. Significant translational gaps persist, including a limited understanding of inhaled delivery barriers, insufficient long-term safety data for repeated dosing regimens, and the poor predictive value of healthy rodent models. While AI-guided lipid discovery, biodegradable formulations, and active targeting strategies offer considerable promise, clinical success will demand rigorous validation in disease-relevant preclinical models.