SORT LNPs encapsulating Cas9 mRNA achieve efficient editing in skeletal muscle in a dystrophic mouse model

Mar 12, 2026Molecular therapy : the journal of the American Society of Gene Therapy

Targeted lipid nanoparticles carrying gene-editing mRNA enable effective muscle editing in a mouse model of muscular dystrophy

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Abstract

The optimized selective organ targeting (SORT) lipid nanoparticles resulted in 40% restoration of Telethonin expression in treated muscle.

Gene editing using lipid nanoparticles (LNPs) may enhance delivery of gene editing tools to skeletal muscle.
Different types of cargo within the LNPs influenced their size, distribution to surrounding muscle groups, and editing efficiency.
Ribonucleoprotein (RNP) and messenger RNA (mRNA) formulations triggered distinct immune responses when administered multiple times.
The study utilized a LGMDR7 mouse model with a TCAP mutation to evaluate the effectiveness of the gene editing approach.

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Limb Girdle Muscular Dystrophy (LGMD) is the fourth most common type of muscular dystrophy. Gene editing holds promise for treating neuromuscular disorders such as LGMD, but clinical translation remains challenging due to lack of complementary delivery tools for skeletal muscle. Lipid nanoparticles (LNPs) offer a promising platform for transient delivery of gene editing reagents as mRNA or ribonucleoprotein complexes (RNPs) to skeletal muscle but editing efficiencies remain modest. While lipid compositions have been optimized to improve delivery to muscle, the impact of cargo type on editing efficiency, biodistribution and immune response has not been evaluated. Here we demonstrate that selective organ targeting (SORT) LNPs encapsulating optimized Cas9 cargo facilitate efficient, local delivery to skeletal muscle. Using a LGMDR7 mouse model harboring a mutation in TCAP as a proof-of-concept target, we show that LNP cargo type impacts LNP size, delivery to neighboring muscle groups and editing efficiency. RNP and mRNA LNPs also provoked distinct innate and adaptive immune responses upon repeated dosing. The optimized SORT LNP platform resulted in 40% restoration of Telethonin expression in treated muscle. Overall, these findings offer valuable insights for the continued development of LNP-based gene editing reagents to facilitate disease-modifying interventions for neuromuscular diseases.