RNA therapeutics and their delivery methods: a paradigm for haemophilia management

Haemophilia management is currently undergoing a paradigm shift from traditional protein replacement to RNA modalities and their delivery. This review provides a critical analysis of RNA-based therapeutics (specifically small interfering RNA (siRNA), mRNA and CRISPR/Cas9) as a versatile paradigm distinct from DNA ones. We synthesise clinical and preclinical data to contrast these modalities: siRNA strategies (e.g. fitusiran) have indicated ∼90% reductions in bleeding rates by rebalancing haemostasis independent of factor deficiency; lipid nanoparticles (LNPs)-mRNA platforms offer tuneable, transient factor production without genomic integration risks; and CRISPR-based editing aims for permanent correction (up to 170% coagulation factor IX, FIX expression in preclinical studies) but necessitates rigorous monitoring for off-target effects. Crucially, this article dissects the non-viral delivery landscape determining the clinical viability of these cargos. We evaluate LNPs as the current clinical gold standard for hepatic delivery, contrasting them against emerging polymeric systems, aptamer conjugates and exosomes designed to overcome rate-limiting barriers such as endosomal entrapment and renal clearance. By juxtaposing the immunogenic limitations of viral vectors, we conclude that next-generation RNA therapeutics, enabled by LNPs and GalNAc-conjugation, offer a strategic pathway to overcome the durability gap observed in haemophilia A and expand treatment access to patients currently excluded by viral seroprevalence.