Alexey V. Yaremenko, Nadezhda A. Pechnikova, Chuang LIU
High Resolution Image Download MS PowerPoint Slide Lung cancer tops the list of the deadliest malignancies, consistently resisting conventional therapies and fueling the urgent pursuit of novel treatment strategies. Messenger RNA (mRNA) nanomedicines are rapidly expanding from pandemic vaccinology to oncology, but achieving efficient and targeted delivery to the lung continues to be a significant obstacle. This Mini-Review highlights advances that enable lung-focused mRNA therapeutics. We show extracellular and intracellular barriers, including mucus, surfactant, alveolar macrophages, and endosomal sequestration. We outline how ionizable lipids, polymer–lipid hybrids, extracellular-vesicle mimetics, and selective organ-targeting chemistry overcome these barriers. We overview the therapeutic payload spectrum, from multiepitope vaccines and antibody factories to tumor-suppressor restoration and in vivo gene editing, highlighting first-in-human data in lung cancer. We discuss persistent bottlenecks: off-target editing, cytokine toxicity, and manufacturing speed and propose design rules to accelerate translation. By integrating sequence-level mRNA design with precision nanocarriers, mRNA technology can benefit lung cancer therapy.