Optimization of lipid nanoparticle components and microfluidic parameters for intramuscular circRNA delivery with reduced hepatic off-targeting.

Authors

Jie Yang, Yijia Hao, Siying Long, Youkui Huang, Gong Wang, Chenxing Yan, Jingxuan Piao, Bowen Wu, Guangyan Huang, Xuexiang Han

Published in

Lab on a chip. Sep 22, 2026. Epub Sep 22, 2026.

Abstract

Circular RNA (circRNA) represents a promising class of RNAs for sustained protein expression and vaccine applications. However, current lipid nanoparticle (LNP) platforms remain poorly optimized for efficient intramuscular circRNA delivery, as they are primarily designed for the delivery of small interfering RNA and linear messenger RNA with strong off-target expression in the liver. In this study, based on the clinical benchmark SM-102 LNP, we systematically optimized lipid components and microfluidic parameters for better intramuscular circRNA delivery. Through in vitro and in vivo screening of a variety of phospholipids and sterols, we identified a 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)- and cholesterol-based formulation, which demonstrated improved storage stability and enhanced intramuscular transfection while minimizing hepatic off-target expression. Using ovalbumin as a model antigen, we proved that this formulation-based vaccine elicited more balanced Th1/Th2 immune responses with reduced liver toxicity. Together, this study successfully develops an optimized formulation with reduced hepatic off-target effects, which holds great promise for the intramuscular delivery of circRNA-based vaccines and therapeutics.

PMID:
42770725
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.

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