Abstract

The widespread application of lipid nanoparticles (LNPs) as mRNA delivery vectors is constrained by the intrinsic trade-off between delivery efficacy and inflammatory reactogenicity. To address this limitation, we engineered a safe and potent LNP-mRNA delivery system by leveraging the dual activities of α- tocopherol (TP). Capitalizing on its well-documented anti-inflammatory and immunomodulatory properties, we hypothesized that incorporating TP or its derivatives into LNPs would concurrently mitigate carrier-induced inflammation and enhance antigen-specific immunogenicity. Our results demonstrate that TP succinate (TPS)-modified LNPs significantly improved in vitro mRNA delivery, achieving up to a 9.5-fold increase in protein expression alongside enhanced cellular uptake, without compromising biocompatibility. Following immunization, TPS-LNPs markedly reduced acute inflammatory reactogenicity, as evidenced by a threefold lower serum IL-6 level at 6 h compared to the standard formulation in blank-LNP groups, and by significantly attenuated cytokine levels in mRNA-loaded groups. In vivo , TPS-LNPs elicited robust and balanced immune responses, characterized by potent humoral immunity and enhanced antigen-specific T cell activation. Mechanistically, the enhanced immunogenicity was associated with upregulated CD40 expression on antigen-presenting cells. Importantly, the anti-inflammatory attributes of TP derivatives conferred an excellent safety profile, with no evidence of significant tissue damage or systemic toxicity. Our findings advocate for a functionalization paradigm in LNP design, wherein α -tocopherol derivatives serve as intrinsic modulators to recalibrate innate immunity, thereby proposing a new design benchmark for simultaneously safe and potent mRNA delivery.