Hybrid polymer nanocarriers enable efficient inhaled mRNA vaccine delivery to the lungs

Novel hybrid polymer nanocarriers enable effective vaccine delivery in the lungs and the targeted activation of immune cells.

An LMU research team led by Professor Olivia M. Merkel, Chair of Drug Delivery at LMU, have developed a new delivery system for inhalable mRNA vaccines. Published in the journal Cell Biomaterials, the study presents a novel combination of poly(lactic-co-glycolic acid) (PLGA) and poly(β-amino esters) (PBAEs) designed to overcome key biological barriers in the lungs.

"Effective mucosal vaccination via inhalation requires carrier systems that can penetrate airway mucus while protecting the fragile RNA molecules they carry," explains Merkel. Once the lung barrier is overcome, the nanocarriers have to escape from the tiny vesicles (endosomes) that are transporting them and efficiently introduce (transfect) the mRNA into immune cells, which then present the corresponding antigens on their surface.

Stable and efficient transport system

LMU team engineered a system that achieves these goals through a spatiotemporally coordinated mechanism. The researchers demonstrated that their hybrid nanoparticles efficiently transfect the targeted immune system cells, a critical requirement for robust immune activation, and support both antigen presentation and immune cell maturation. Moreover, the particles successfully crossed the mucus barrier and enabled mRNA expression in ex vivo human precision-cut lung slices, a highly relevant human lung model.

"A major advantage of the new system is its robustness during aerosolization," says Merkel. After vibrating-mesh nebulization, the PLGA/PBAE nanocarriers retained higher transfection efficiency than clinically approved lipid nanoparticles, highlighting their suitability for inhaled vaccine applications. "Our findings show that data-driven polymer design can address multiple delivery barriers simultaneously. This hybrid platform offers a promising alternative to lipid nanoparticles for next-generation pulmonary mRNA vaccines."

The study was supported by the Bavarian Research Foundation and the European Research Council (ERC). According to the authors, it makes an important contribution to the development of safe, effective, and patient-friendly mucosal vaccines.