Target-Product and Translational Design Principles for Inhalable RNA Nanomedicines.

Inhalable ribonucleic acid (RNA) nanomedicines are emerging as versatile therapeutics for respiratory diseases and pulmonary metastases, enabling localized delivery of messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotides, microRNA (miRNA) mimics, self-amplifying RNA, and genome-editing systems. This review synthesizes the available evidence and argues that the field has moved beyond asking whether RNA can reach the lungs. The more consequential translational question is whether RNA cargo, nanocarrier, excipients, manufacturing process, inhalation device, and pulmonary target cell can be integrated into a reproducible therapeutic product. Current research demonstrates progress in disease-corrective mRNA expression, silencing of inflammatory and fibrotic pathways, mucosal vaccination, antiviral therapy, and localized cancer treatment, alongside advances in ionizable lipid nanoparticles, lipid-polymer hybrids, chitosan and polyethyleneimine (PEI) polyplexes, dendrimers, peptide carriers, biomimetic systems, and dry-powder formulations. Translational maturity, however, remains uneven. Many studies demonstrate carrier feasibility, reporter expression, or preclinical activity, whereas fewer establish device-compatible aerosolization, preservation of RNA integrity during processing, traversal of pulmonary barriers, target-cell engagement, repeat-dose tolerability, and clinically meaningful benefit. Development should therefore be target-defined, analytically gated, device-specific, and outcome-centered. Inhalable RNA nanomedicines are best understood as integrated pulmonary products whose success depends on preserving RNA function throughout manufacturing, aerosolization, post-deposition barrier navigation, intracellular delivery, and disease-relevant pharmacodynamic activity.