Reduction of cellular toxicity with hybrid nanoparticles for mRNA delivery

Building on the success of COVID-19 vaccine development, lipid nanoparticles (LNPs) have emerged as leading vehicles for mRNA delivery in a range of therapeutic applications. Naturally-occurring extracellular vesicles (EVs), which share similar physical properties with LNPs, present a promising alternative platform because of their relative stability and lower immunogenicity. A key challenge common to both EVs and LNPs is enabling efficient vesicle - cell interactions and establishing a polarized permeability pathway required for effective cargo transfer. Membrane recognition and intercalation are essential for the function and delivery capacity of both systems, regardless of their complexity. In this study, we leveraged recent advances to create hybrid extracellular vesicles (HEVs) by using LNPs to load mRNA into EVs. We characterized HEV formation using Forster resonance energy transfer (FRET), cryo-electron microscopy (Cryo-EM), and super-resolution microscopy, and demonstrated their ability to deliver mRNA to recipient cells. In both, in vitro and in vivo models, HEVs exhibited superior transfection efficiency compared to conventional LNPs composed of synthetic lipids, while significantly reducing LNPs cytotoxicity - a not-well-recognized limitation of synthetic lipid-based systems. These results highlight HEVs as a safer and more effective alternative for mRNA and small molecule delivery. Future therapeutic strategies could involve isolating EVs from patients, hybridizing them with synthetic lipid carriers loaded with therapeutic cargo, and reintroducing them for personalized treatment.