Novel α-mannose-functionalized poly(β-amino ester) nanoparticles as mRNA vaccines with increased antigen presenting cell selectivity in the spleen.

mRNA vaccination has emerged as a prominent therapy for the future of medicine. Despite the colossal advance in this technology and worldwide efficacy proof ( ca. COVID vaccines), mRNA carriers still lack cell/tissue specificity, leading to possible side effects, and reduced efficacy among others. Herein we make use of the ubiquitous affinity of antigen-presenting cells (APC)s for glycosides to achieve specific targeting. To achieve this goal, we designed a new generation of α-mannosyl functionalized oligopeptide-terminated poly(β-aminoester). Fine formulation of these polymers with mRNA resulted in nanoparticles decorated with surface-exposed α-mannoses with sizes around 180 nm and positive surface charge. Notably, these particles maintained their properties after freeze-drying and subsequent redispersion. Finally, our mRNA carriers preferentially targeted and transfected APCs in vitro and in vivo . In conclusion, we demonstrated, at a preclinical level, that the mannose functionalization enables more selective targeting of APCs and, thus, these polymer and nanoparticles are candidates for a new generation of mRNA immunotherapy vaccines.