RNA interference (RNAi) is an ancient biological mechanism used to defend 
against external invasion. It theoretically can silence any disease-related 
genes in a sequence-specific manner, making small interfering RNA (siRNA) a 
promising therapeutic modality. After a two-decade journey from its discovery, 
two approvals of siRNA therapeutics, ONPATTRO® (patisiran) and GIVLAARI™ 
(givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the 
long-term pharmaceutical history of human beings, siRNA therapy currently has 
set up an extraordinary milestone, as it has already changed and will continue 
to change the treatment and management of human diseases. It can be administered 
quarterly, even twice-yearly, to achieve therapeutic effects, which is not the 
case for small molecules and antibodies. The drug development process was 
extremely hard, aiming to surmount complex obstacles, such as how to efficiently 
and safely deliver siRNAs to desired tissues and cells and how to enhance the 
performance of siRNAs with respect to their activity, stability, specificity and 
potential off-target effects. In this review, the evolution of siRNA chemical 
modifications and their biomedical performance are comprehensively reviewed. All 
clinically explored and commercialized siRNA delivery platforms, including the 
GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design 
principles are thoroughly discussed. The latest progress in siRNA therapeutic 
development is also summarized. This review provides a comprehensive view and 
roadmap for general readers working in the field.