Engineering the airway regenerative niche: conditioning, biomaterials, and cell therapies for epithelial replacement

Airway epithelial cell transplantation offers a promising regenerative strategy for diseases such as cystic fibrosis, primary ciliary dyskinesia, and chronic rhinosinusitis, which are characterised by epithelial injury, mucus stasis, and persistent inflammation. Advances in the expansion and differentiation of airway basal cells have renewed optimism for clinical translation. However, therapeutic success remains limited by early graft loss, infection, and poor cell retention within the high-shear, mucus-rich airway environment. This review presents a unified translational framework that integrates airway conditioning, biomaterials, and epithelial cell therapy to address key barriers to engraftment. Conditioning is defined as a time-limited intervention that establishes a permissive “window of receptivity” by transiently reducing microbial burden, inflammation, oxidative stress, and fibrotic signalling during the critical early period following cell delivery. Biomaterial strategies, including clinically relevant hydrogels and extracellular matrix scaffolds, are discussed as approaches to improve epithelial coverage, enhance cell residence time, and enable localised delivery of adjunctive factors, while minimising luminal obstruction. We further describe how these components can be combined with autologous or induced pluripotent stem cell-derived airway basal cells to form an integrated therapeutic approach. This combination product spans both manufacturing and procedural domains, incorporating cells, matrices, conditioning regimens, and delivery techniques. We summarise preclinical and emerging clinical evidence supporting these approaches and examine key translational considerations, including safety, scalability, and regulatory expectations. By integrating biological, material, and clinical strategies, the framework presented in this review provides a pragmatic pathway toward durable airway epithelial regeneration and supports the development of first-in-human studies in the sinonasal and proximal airway.