REpurposing lung Surfactant Protein B for Inhalation therapy with RNA therapeutics

ongoing

RESPIRNA aims to repurpose lung surfactant protein B (SP-B) to promote the cytosolic delivery of RNA in lung-related target cells. RNA therapeutics, including small interfering RNA (siRNA) and messenger RNA (mRNA), are poised to revolutionize medicine. However, despite a clear unmet medical need in many lung diseases, no RNA formulations are currently available for pulmonary administration. To unlock the full therapeutic potential of RNA drugs, safe and efficient nanomedicines that can deliver them inside target cells are required. SP-B is a key component of pulmonary surfactant, essential for mammalian breathing. In contrast to the general belief that pulmonary surfactant constitutes an important extracellular barrier for macromolecular drug delivery in the lung, I recently discovered a previously unknown property of SP-B in its ability to promote transmembrane delivery of RNA inside cells. Here, I aim to repurpose this biomaterial for intracellular RNA delivery, (1) by exploring SP-B's cellular mode-of-action towards improved cytosolic delivery of RNA, (2) by designing multifunctional and multicomponent lung surfactant nanocarriers and (3) by applying these nanocarriers for RNA delivery in the lung, using models of obstructive lung disease. Gaining mechanistic insight into how an endogenous membrane-active protein like SP-B can mediate cytosolic RNA delivery will allow me to maximize SP-B mediated delivery of promising RNA therapeutics and will fuel rational design of lung surfactant inspired nanocarriers for inhalation therapy. Beyond RESPIRNA, I anticipate that such nanocarriers will be more generically applicable for a wider variety of membrane-impermeable drugs, nanomedicines and pathologies.