A novel approach to delivering transforming growth factor-beta (TGF-β) mRNA directly to the lower lungs demonstrates promising strides for treating lung injuries, according to recent research conducted by scientists from the University of Pennsylvania and Rutgers University.
The study addresses significant shortcomings existing therapies face, which primarily target the upper airways, leaving the lower lung parenchyma area inadequately treated for conditions such as acute lung injury (ALI). With approximately 200,000 new ALI diagnoses annually leading to severe morbidity and mortality, effective delivery methods aimed at lower lung regions are critically needed.
Investigators have developed one-component ionizable amphiphilic Janus dendrimers, termed IAJDs, which serve as vehicles to transport TGF-β mRNA to the desired area within the lung. This delivery system allows for effective and safe mRNA therapeutic application, showcasing potential to bridge the clinical gap for patients suffering from parenchymal lung injury.
“This study highlights a method for precise, effective, and safe delivery of TGF-β mRNA to the lung,” the authors stated, emphasizing the targeted capability of IAJDs.
The innovative formulation of IAJDs consists of functional hydrophilic and hydrophobic dendrons, which are able to self-assemble as nanoparticles amenable to mRNA encapsulation. Previous methods primarily involved four-component lipid nanoparticles, which proved unsuccessful for targeted lung delivery. Conversely, IAJDs manifest strong lung specificity, allowing these dendrimers to not only carry mRNA but also effectively deliver it—which has previously posed challenges.
Research findings indicated impressive results with IAJD34, leading to significant mRNA expression localized within murine lungs. Units of luciferin mRNA were primarily concentrated within the lungs following intravenous injections, highlighting the efficacy of the delivery system.
“We confirm...that IAJDs can be utilized for the successful and targeted delivery of cytokine mRNA diffusely throughout the lung,” noted the researchers, underlining the delivery method’s clarity and efficiency.
The detailed investigation involved administering formulations containing increasing doses of TGF-β mRNA to analyze response variables post-injection. Results indicated proportional mRNA presence across reduced inflammatory responses within treated mice, maintaining safety profiles without significant toxicity. This aspect is particularly pertinent as long-term exposure to TGF-β could lead to fibrosis—addressing other clinical issues raised by persistent elevation of the cytokine.
“The delivery of TGF-β was transiently expressed over the course of 48 hours, which is important as long-term delivery of TGF-β can lead to significant fibrosis,” shared the authors, emphasizing the need for controlled expression within therapeutic ranges.
Through this research, IAJDs emerge as promising candidates for genetic nanomedicine and potential lung-based nanotherapeutics. They open pathways for future interventions against ALI and other pulmonary ailments demanding targeted delivery systems, setting the stage for upcoming clinical applications.
Overall, these findings may herald advancements through enhanced response analyses post-therapy, capturing the essence of how targeted delivery systems advance lung treatment strategies.