Frontiers in Medicine · Oct 30, 2026
RNA therapeutics for muscle wasting: bridging target validation and muscle-directed delivery
By Ye Li, Xiaolu Zhang, Xiaoyan Liu
Muscle wasting accompanies aging, immobilization, cancer cachexia, chronic disease, and neuromuscular disorders, but its biological heterogeneity has impeded development of broadly effective therapies. Recent studies implicate circular RNAs, N6-methyladenosine, and coding-non-coding RNA crosstalk in the control of myofiber size, regeneration, and metabolic adaptation, while advances in oligonucleotide chemistry, messenger RNA, gene editing, extracellular vesicles, and lipid nanoparticles have expanded the therapeutic toolkit. The key translational problem is no longer a shortage of candidate RNAs, but failure to connect causal target validation with active, muscle-directed delivery and meaningful functional recovery. This Mini Review integrates these dimensions and uses mechanical disuse and reloading as an indication-proximal (modeling the target condition) test case. Causal studies of METTL3, lncMAAT, and circDdb1 illustrate increasing target maturity, whereas direct disuse evidence remains limited to a few carrier-enabled programs, including intramuscular miR-194 nanospheres and engineered extracellular vesicles delivering CRISPR/Cas9 genome-editing machinery targeting miR-29b. Evidence from cachexia, metabolic disease, muscular dystrophy, and injury supports feasibility of extracellular vesicles, lipid nanoparticles, antibody-oligonucleotide conjugates, antisense oligonucleotides, messenger RNA, and CRISPR cargoes, but cannot be assumed to translate to immobilized or aged muscle. We propose a stage-gated framework in which target direction, cell specificity, treatment duration, multi-muscle exposure, intracellular cargo release, sequence-specific target engagement, functional endpoints, repeat-dose safety, and product quality are evaluated as a connected evidence chain. For reversible and geriatric wasting, transient RNA therapeutics are most plausibly developed as time-limited adjuncts to rehabilitation and nutrition. The reviewed disuse programs provide preclinical proof of concept, but lack clinical validation.