Elucidating membrane interactions of non-lamellar lipid nanovectors for nucleic acids upon acidification.

Nucleic acid (NA) therapeutics hold great potential for personalized medicine, but their clinical success depends on the development of effective delivery vectors. To ensure efficient NA delivery, such vectors need to escape endosomes, releasing NA into the cytosol. Non-lamellar lipid nanoparticles (NLLNPs) possess a highly curved bilayer structure, potentially boosting endosomal escape by enhancing membrane destabilization. Through a microfluidic approach, we developed novel NLLNPs which display pH-activated structural responsivity, potentially affecting the interaction with endosomal membranes. Leveraging static and Time-Resolved SAXS, we aim to investigate NLLNPs structural evolution and membrane interactions upon acidification, as encountered in endosomes. Results will provide fundamental knowledge on the role of lipid nanoparticles structure in the interaction with model endosomal membranes, contributing to inform the design of more efficient vectors for NA delivery.