mRNA lipid nanoparticles (LNPs) have emerged as a number one supply system for mRNA-based vaccines and therapeutics. Nonetheless, a big limitation of this method is the presence of poly(ethylene) glycol (PEG). It’s extensively recognized that repeated doses of PEG-based therapeutics can induce an anti-PEG antibody response, resulting in the accelerated blood clearance (ABC) of LNP therapeutics requiring frequent dosing, as anti-PEG antibodies have been discovered current in a big proportion of the inhabitants. To deal with this subject, we developed a mouse mannequin for LNP clearance after a repeated dose. We then synthesised LNPs with the PEG part changed by a library of hydrophilic polymers: poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), POEGMA-methacrylic acid (POEGMA (–)), POEGMA-2-(dimethylamino)ethyl methacrylate (POEGMA (+)), poly(N,N-dimethylacrylamide) (PDMA), and poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA). Our outcomes demonstrated that each one three POEGMA LNPs, particularly POEGMA (+) LNPs, exhibited minimal ABC impact after two weekly doses; in distinction, PDMA LNPs demonstrated considerably decrease clearance within the presence of anti-PEG antibodies. This research highlights the potential of PEG-free polymer-LNPs as promising mRNA carriers that keep away from speedy clearance with repeated administration.