Spliceosome-directed Antisense Nanocomplexes for Aberrant Transcript-Selective Gene Repression: A Concise Review

Aberrant pre-mRNA splicing is a key molecular mechanism driving numerous genetic, neurodegenerative and oncologic diseases. Mutations affecting splice sites or regulatory elements can generate mis-spliced transcripts that encode dysfunctional proteins. Antisense oligonucleotides (ASOs) offer therapeutic potential by modulating splicing at the RNA level without altering DNA, but their clinical translation is limited by poor cellular uptake, rapid clearance and inefficient nuclear delivery. Spliceosome-directed antisense nanocomplexes have emerged as an innovative solution, enhancing ASO stability, specificity and intracellular trafficking. This review presents a mechanistic overview of spliceosomal regulation and aberrant splicing, followed by a critical analysis of ASO chemistries and delivery hurdles. We evaluate a range of nanocarriers — lipid nanoparticles (LNPs), polymers, dendrimers and peptide-based vectors — for their roles in improving ASO delivery and efficacy. Preclinical data from disorders such as spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), [Formula: see text]-thalassemia and glioblastoma demonstrate the therapeutic promise of these platforms. We also address translational barriers, including immunogenicity, off-target effects and manufacturing challenges, along with engineering strategies to overcome them. Spliceosome-directed antisense nanocomplexes represent a promising frontier in RNA therapeutics for splicing-related diseases.