Cell and Gene Therapy in Lung Transplantation: From Experimental Promise towards Clinical Translation

Lung transplantation (LTx) remains the only definitive therapy for selected patients with end-stage lung disease, yet outcomes are limited by early ischemia-reperfusion injury (IRI) and primary graft dysfunction (PGD), and by chronic lung allograft dysfunction (CLAD) as the leading cause of late graft failure. These entities share overlapping injury and repair pathways, including alveolocapillary barrier disruption, microvascular dysfunction, innate immune activation, and maladaptive remodeling, which remain incompletely controlled by current perioperative management and systemic immunosuppression. This review summarizes cell and gene therapy approaches in LTx and frames these strategies around the IRI/PGD-to-CLAD continuum. Stromal cell therapies, regulatory immune cell approaches, and cell-free or cell-derived products such as extracellular vesicles and mitochondrial transfer are discussed, with emphasis on route, dose, persistence, and the graft microenvironment as determinants of biological activity. Gene modulation strategies and delivery platforms relevant to the lung, including viral vectors, lipid nanoparticles, and virus-like particles, are outlined, together with preclinical gene therapy strategies targeting IRI and allograft rejection. Ex vivo lung perfusion (EVLP) is highlighted as a practical window for organ-confined delivery and early mechanistic assessment prior to implantation. Key translational considerations are outlined, including product characterization and potency, clinically interpretable dosing, and the need for harmonized endpoints and pharmacodynamic readouts to improve comparability across studies.