Hepa-SENS: ASGPR-mediated hepatocyte delivery and attenuated unwanted immune recognition for nucleic acid therapeutics

An optimal nucleic acid delivery system for hepatic therapeutics should demonstrate consistent pharmacological performance across both normal and diseased hepatic microenvironments, enabling repeated administration with favorable safety profiles. Given the disease-sensitive and relatively low expression of low-density lipoprotein receptor (LDLR) on hepatocytes and compared to the abundant and disease-resilient expression of asialoglycoprotein receptor (ASGPR), ASGPR-mediated drug delivery presents a compelling strategy for liver diseases. Here, we introduce Hepa-SENS, a next-generation polymer-lipid hybrid nanoparticle platform enabling robust ASGPR-mediated hepatocyte delivery without ligand conjugation. Its biodistribution, hepatocyte selectivity, receptor dependence, repeated-dose activity, and therapeutic performance were evaluated in healthy and fibrotic mouse liver models. Hepa-SENS demonstrates strong, hepatocyte-selective transgene expression of mRNA payload preserved under disease conditions, such as high-fatty liver and liver fibrosis, and across multiple species, including non-human primates. In long-term repeat-dose regimens, Hepa-SENS sustained mRNA-driven protein expression without inducing antibodies to the delivery system, enabling greater consistency than conventional lipid nanoparticles (LNPs). In fact, in a liver fibrosis mouse model, where a reduction of LDLR is observed as fibrosis develops, Hepa-SENS outperformed conventional LNPs in delivering therapeutic hepatocyte nuclear factor 4 alpha mRNA and attenuating disease progression. In conclusion, Hepa-SENS represents a robust and versatile delivery platform for nucleic acid therapeutics targeting hepatocytes under disease-relevant conditions via ASGPR-dependent mechanisms. Its repeated-dosing-compatible design supports durable treatment strategies for chronic liver diseases.