Multivalent ionizable lipid-polypeptides for tumor-confined mRNA transfection.

ABSTRACT: mRNA therapeutics is revolutionizing the treatment concepts toward many diseases including cancer. The potential of mRNA is, however, frequently limited by modest control over site of transfection. Here, we have explored a library of multivalent ionizable lipid-polypeptides (MILP) to achieve robust mRNA complexation and tumor-confined transfection. Leveraging the multivalent electrostatic, hydrophobic, and H-bond interactions, MILP efficiently packs both mRNA and plasmid DNA into sub-80 nm nanoparticles that are stable against lyophilization and long-term storage. The best MILP@mRNA complexes afford 8-fold more cellular uptake than SM-102 lipid nanoparticle formulation (SM-102 LNP), efficient endosomal disruption, and high transfection in different cells. Interestingly, MILP@mLuc displays

SUBMITTER: Zhao X 

PROVIDER: S-EPMC11754973 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature