Messenger RNA (mRNA) therapeutics are a promising strategy to combat diverse diseases. Traditional lipid nanoparticle (LNP) formulations for mRNA delivery contain poly(ethylene) glycol (PEG), a polymer widely used in drug delivery carriers but that recently has been associated with efficacy and immunogenicity concerns. Here we report poly(carboxybetaine) (PCB) lipids as surrogates for PEG-lipids used in mRNA formulations. In vitro studies with immortalized and primary cells show that PCB-containing LNPs have higher mRNA transfection efficiency than PEG-containing LNPs across different formulations. Moreover, primary cell engineering and in vivo immunization studies in mice further demonstrate greater therapeutic efficacy of PCB-containing LNPs over their PEG counterparts. Mechanistic assays show that this improvement is attributed to enhanced endosomal escape of PCB-containing LNPs. These formulations exhibit a safe immunotoxicity profile and effectively mitigate the accelerated blood clearance effect that has been observed for PEG-containing LNPs, enabling repeated administrations without efficacy loss. Overall, these findings highlight PCB-containing LNPs as a potent and safe mRNA delivery platform for clinical applications.