Targeted conjugates, such as GalNAc-siRNA complexes, exploit specific receptors on hepatocytes, allowing for non-viral delivery directly to the liver with high specificity. These drugs validate the platform’s ability to reduce pathogenic protein production with durable effects, requiring only periodic dosing.
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To overcome this, lipid nanoparticles (LNPs) and polymeric carriers are frequently used to protect the payload and facilitate endosomal escape. Ongoing trials are expanding into oncology and viral diseases, exploring combinations with immune checkpoint inhibitors.
The primary concern is the activation of the innate immune response, particularly through Toll-like receptors, which can cause inflammation or cytokine release. Conjugation technologies are being developed to target lung tissue, tumors, and the central nervous system.
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Researchers and clinicians are increasingly viewing these short duplexes as potent therapeutic tools capable of targeting previously undruggable transcripts. Off-target effects can occur when the sirna seed region binds to transcripts with partial complementarity, inadvertently silencing non-target genes.
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