构建自扩增 mRNA-LNP 复合物递送苯丙氨酸羟化酶及其对苯丙酮尿症基因治疗的疗效评价

Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficient phenylalanine hydroxylase (PAH) activity, with current pharmacotherapies showing limited response rates and age-dependent restrictions. We compared two liver-targeted lipid nanoparticle formulations delivering PAH-encoding mRNA-a self-amplifying construct (saRNA) and a conventional non-replicating counterpart (nr-mRNA)-in Pah-knockout mice. Both constructs reduced circulating phenylalanine (Phe) after a single intravenous injection. The saRNA formulation achieved comparable efficacy at one-sixth the nr-mRNA dose and maintained physiological Phe levels for 14 days, whereas nr-mRNA produced only transient reductions. Repeated saRNA administration was well tolerated, with no detectable immunogenicity or hepatic toxicity. These results establish that saRNA-mediated PAH replacement provides sustained activity with substantial dose reduction, overcoming the short-lived effect of non-replicating mRNA. This platform may inform broader strategies for durable enzyme therapy in inherited metabolic diseases requiring liver-restored function.