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Tetrahedral DNA Nanostructure-delivered Suppressor tRNA Ameliorates Nephropathy in COL4A5 Nonsense Mutation-mediated Alport Syndrome Mice

ABSTRACT: Nonsense mutations introduce premature termination codons (PTCs) that trigger mRNA degradation and underlie genetic diseases, including Alport syndrome (AS). Suppressor tRNAs (sup-tRNAs) are potential therapies for such disorders, as they can precisely readthrough PTCs and restore full-length protein synthesis. For AS caused by COL4A5 nonsense-mediated deficiency, we developed a TDN-sup-tRNA delivery strategy using tetrahedral DNA nanostructures (TDNs) characterized by excellent biocompatibility and renal targeting. In a Col4a5-R471X mouse model, TDN-sup-tRNA achieved high readthrough efficiency, restoring COL4A5 protein expression and reconstituting glomerular basement membrane integrity. Notably, proteinuria was reduced to 35% of baseline within four weeks. Compared with AAV2/9-mediated delivery, this system exhibited enhanced renal targeting and superior therapeutic efficacy over a one-month treatment period, without detectable toxicity. Collectively, this strategy represents a safe and effective non-viral RNA therapeutic approach for precise correction of nonsense mutation–associated renal diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Dan Hong

LAB HEAD: Qing Xia

PROVIDER: PXD078106 | Pride | 2026-05-13

REPOSITORIES: Pride

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