14. Yan Tang, PhD

Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) co-formulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to lung. Different pulmonary cell types can also be targeted by simply tuning the head-group structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based mRNA therapy for the treatment of lymphangioleiomyomatosis (LAM), a low-grade neoplasm that primarily affects women, using a preclinical model of LAM. This destructive lung neoplasm is caused by loss-of-function mutations in tumor suppressor genes TSC1 (Tuberous Sclerosis Complex 1) or TSC2 (more common). Our lung-targeting LNP exhibited highly efficient delivery of wildtype Tsc2 mRNA for the restoration of TSC2 tumor suppressor in tumor lesions and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA replacement as a promising therapeutic intervention for the treatment of LAM.