Controlled Degradable Polymer Carriers for mRNA Vaccination: From Pathogens to Personalized Cancer Immunotherapy

The tragic outbreak of the COVID-19 pandemic stimulated research to go beyond common grounds and develop powerful vaccines against the SARS-CoV-2 virus. A new vaccine technology based on messenger RNA (mRNA) was translated into almost one billion patients and saved millions of lives. It addresses the needs of rapid, scalable and adaptable vaccine production. However, mRNAs require potent nanocarriers to prevent the RNA strands from extracellular degradation and enable their uptake into antigen-presenting cells. During urgent development, established lipid-based nanoparticles (LNPs) were used for mRNA encapsulation, yet, they provided limited long-term stability and required strict temperature storages, which prevented their distribution to locations with no cold storage options. Moreover, several patients experienced hard-to-control immunological adverse effects that were associated with some of the lipid components. In my ERC proposal, I therefore want to pioneer a novel and unprecedented macromolecular approach that will overcome these issues and introduce polymer-based and lipid-free, lyophilizable nanocarriers for intelligent mRNA delivery. I will generate self-immolative poly(carbonate)s with reductive decationizable features for controlled RNA complexation, as well as stimuli-responsive release and carrier depolymerization upon entry into antigen-presenting cells. Co-delivery of small molecule immune modulators will enable precise control over quality and quantity of the pursued humoral and cellular immune responses. Moreover, reversible core-crosslinking and surface conjugation with relevant targeting units will foster systemic in vivo applications towards immunization against infectious diseases and cancer. Elaborating multi-responsive macromolecular tools on an mRNA-binding polymer will become a groundbreaking asset for mRNA delivery, circumvent today's still not overcome hurdles and enhance its access to and acceptance by the general public.