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

作者：Yanyang Chen, Wei He, Shifeng Ling, Yang Zhou, Jie Chen, Yawei Du, Ran Mo, Wenguo Cui · 发表于：Bioactive Materials · 年份：2026 · DOI：10.1016/j.bioactmat.2026.01.007 · 被引用次数：1 · 研究领域：RNA Interference and Gene Delivery、RNA modifications and cancer、Protein purification and stability

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 engineer...