From Laboratory to Clinic: Translational Challenges, Lessons, and Future Strategies for microRNA Delivery Systems.

Abstract

MicroRNA (miRNA)-based therapeutics can modulate disease-associated gene networks by restoring protective miRNAs or inhibiting pathogenic miRNAs, yet clinical translation remains limited despite substantial preclinical progress. This review critically evaluates representative clinical and advanced translational programs, including Miravirsen, MRX34, Cobomarsen, Remlarsen, RGLS4326, and farabursen (RGLS8429), to compare molecular designs, delivery approaches, development outcomes, and translational bottlenecks. These programs show that clinical success cannot be explained by delivery efficiency alone, but depends on the interplay among tissue selectivity, intracellular delivery and endosomal escape, immune compatibility, sequence- and network-level pharmacology, PK/PD, and Chemistry, Manufacturing, and Controls (CMC). We also assess emerging strategies, including organ-selective lipid nanoparticles, stimuli-responsive nanocarriers, extracellularvesicle- based systems, and local delivery, with emphasis on their translational potential and remaining validation needs. Drawing on these lessons, we propose a Four-Pillar Framework integrating Delivery Systems, Immune Safety, CMC and Manufacturing Readiness, and biomarker-guided Clinical Design. Together, these principles support coordinated optimization across biological, pharmaceutical, and clinical dimensions rather than isolated improvement of individual delivery parameters.