RNA interference therapeutics for disease-associated proteins: from molecular design to clinical translation

Abstract RNA interference (RNAi) has emerged as a revolutionary therapeutic approach for silencing disease-associated genes with unprecedented specificity and precision. This review examines the molecular mechanisms, design principles, and clinical applications of RNAi therapeutics targeting pathogenic proteins. We analyze the landscape of disease-associated proteins amenable to RNAi intervention, ranging from cardiovascular targets, such as lipoprotein(a) and PCSK9, to neurodegenerative proteins, including tau, alpha-synuclein, and huntingtin. The clinical success of liver-directed RNAi therapeutics, exemplified by FDA-approved drugs such as patisiran, inclisiran, and givosiran, has established a foundation for targeting previously “undruggable” proteins. We discuss optimal RNAi modality selection, advances in delivery systems, and the challenges of extrahepatic targeting. Current clinical development programs demonstrate efficacy rates exceeding 80% protein reduction with infrequent dosing schedules. As delivery technologies advance beyond hepatocytes to other tissues, RNAi therapeutics promise to address a broader spectrum of protein-mediated diseases, representing a paradigm shift toward programmable precision medicine.