Cell stem cellJan 28, 2026

Using lipid nanoparticles to edit genetic mutations causing congenital ichthyosis directly in human skin models

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Topical lipid nanoparticle delivery of a cytosine base editor corrected a common ARCI-causing TGM1 splice mutation in human skin models.

Evidence

This preclinical platform study used human congenital ichthyosis disease models and found about 30% restoration of wild-type transglutaminase 1 activity after skin barrier modulation and topical eTd lipid nanoparticles, with repeated-application toxicity and off-target testing.

Caveat

The evidence is from human skin models rather than treated patients, so clinical durability, efficacy, and safety remain unproven.

Simplified

Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients' quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.