Title : Development of a next-generation hepatocyte-targeted nucleic acid delivery platform evading LDLR dependence and PEG-related immunogenicity
Abstract:
An effective nucleic acid therapeutic delivery system must ensure consistent performance across both healthy and diseased liver conditions, support repeat dosing without inducing toxicity, and minimize immunogenic responses. In hepatic applications, clinical validation of two key hepatocyte receptors—low-density lipoprotein receptor (LDLR) and asialoglycoprotein receptor (ASGPR)—has led to the approval of patisiran (Onpattro) and inclisiran (Leqvio). Given the robust and disease-resilient expression profile of ASGPR, ASGPR-mediated uptake presents a compelling strategy for hepatocyte delivery.
Here, we introduce Hepa-SENS, a polymer–hybrid lipid nanoparticle platform that enables efficient ASGPR-mediated hepatocyte delivery of nucleic acid therapeutics without the need for ligand conjugation. Hepa-SENS demonstrated strong and hepatocyte-selective transgene expression across multiple species (mice, rabbits, and non-human primates). The tissue/cell selectivity and delivery efficiency were preserved under disease-relevant conditions, such as high-fat diet and liver fibrosis models in mice.
In preclinical studies, Hepa-SENS exhibited a superior safety profile compared to conventional LNPs, showing excellent tolerability with no signs of cumulative toxicity. Conventional LNPs are known to trigger anti PEG and anti-phosphocholine antibodies upon repeated administration, leading accelerated clearance, reduced efficacy, and potential hypersensitivity. To mitigate these risks, Hepa-SENS incorporates DOPE in place of DSPC and utilizes a biodegradable PEG-polymer to reduce the likelihood of anti-PEG antibody induction, thereby supporting long-term dosing.
In addition, the Hepa-SENS platform can deliver diverse RNA therapeutics such as siRNA, mRNA as well as CRISPR-based gene-editing payloads without changes to formulation principles. Ai14 reporter mouse study results confirmed that Hepa-SENS demonstrates superior Hepatocyte selective and higher gene-editing efficacy compared to conventional LNPs.
In conclusion, Hepa-SENS represents a robust and scalable delivery platform for nucleic acid therapeutics targeting hepatocytes under disease-relevant conditions via ASGPR-dependent mechanisms. Its immune-evasive design supports durable treatment strategies for chronic liver diseases. Unlike GalNAc-conjugated LNPs, that relies on costly conjugation steps, Hepa-SENS maintains a traditional manufacturing process, ensuring scalability, regulatory compliance, and cost-efficiency.
