Ionizable Coenzyme‐Engineered Lipid/Fiber Microplexes Boost Ribosomal Translation to Improve mRNA Therapy for Degenerative Diseases

作者：Shifeng Ling, Yixiang Zhang, Yanyang Chen, Wei He, Tianqi Wu, Juan Wang, Yingying Wei, Min Lu, Weili Zhao, Qingfeng Li, Yawei Du, Wenguo Cui · 发表于：Advanced Materials · 年份：2025 · DOI：10.1002/adma.202513720 · 被引用次数：8 · 研究领域：ATP Synthase and ATPases Research、RNA modifications and cancer、RNA Interference and Gene Delivery

Mitochondrial dysfunction-mediated ribosomal translation suppression is a hallmark of aging and a major driver of degenerative diseases, limiting mRNA therapy efficacy. Here, ionizable coenzyme Q10 (iCoQ10)-engineered lipid/fiber microplexes (iCLNP@SF) are developed that restore the mitochondrial-ribosomal axis to enhance mRNA translation. iCoQ10 replaces conventional ionizable lipids to form prodrugged lipid nanoparticles (iCLNP), stabilized by injectable polydopamine‑modified short fibers for in situ administration. In vitro efficacy assessments showed that iCLNP@SF synergistically enhanced mitochondrial metabolism and mRNA translation in senescent cells. Further mechanistic studies revealed that iCLNP stabilized mitochondrial membrane potential, suppressed cGAS-STING activation, and reduced eIF2α phosphorylation, thereby enhancing translation. In vivo, iCLNP@SF delivery of Gas6 mRNA increased hair follicle density by ≈50% in an androgenetic alopecia mouse model, while Runx2 mRNA delivery raised new bone formation (BV/TV) to ≈40% in defect models, both markedly outperforming conventional LNPs. Together, these findings highlight a strategy that improves mRNA therapy for degenerative diseases.