Boosting ribosomal translation via ionizable lipid-hydrogel microplexes for localized mRNA therapy

mRNA therapy holds immense promise for regenerative medicine; however, localized endoplasmic reticulum stress (ERS) in damaged tissues can impair the critical process of ribosomal translation. Here, we developed an in situ injectable lipid nanoparticle (LNP)/microsphere complex, also referred to as a lipid-hydrogel microplex (iLMP), with ERS-alleviating functionality to increase ribosomal translation. A vitamin E-derived ionizable lipid was synthesized to replace conventional ionizable lipids in LNPs, whereas porous hydrogel microspheres stabilized the LNPs via physical adsorption. In vitro studies revealed that the iLMPs codelivered vitamin E and mRNA, mitigating ERS and reducing eIF2α phosphorylation, a key translational barrier. Additionally, iLMPs injected in situ rapidly reconstructed the extracellular matrix, promoting tissue repair. In a bone defect animal model, iLMPs significantly enhanced BMP-2 mRNA translation, promoting osteogenesis. In summary, we present a novel in situ injectable mRNA delivery platform that enhances ribosomal translation, offering a promising strategy for tissue regeneration. Currently, no studies have focused on how ERS-induced ribosomal translation limitations may affect the efficacy of mRNA therapeutics. In this work, we address this challenge by introducing a novel ERS-alleviating ionizable lipid and designing a specialized lipid-hydrogel microplex system that integrates LNPs with microspheres. This composite system is specifically engineered to overcome the limitations of mRNA transfection in inflammatory microenvironments. • Innovative iVES Design: iVES serves as the core component of iLMP, not only alleviating ERS but also enabling mRNA condensation and endosomal escape. • iLMP Construction: iLMP contributes to the storage stability of mRNA therapeutics, further enhancing their efficacy. • Exploration of ERS on mRNA Therapeutics: This work is the first to focus on the impact of ERS during the in-situ application of mRNA.