<p>Oligonucleotide therapeutics (ONTs) have emerged as a transformative treatment modality with numerous products approved globally for addressing a variety of diseases. Within this class, siRNAs therapeutics have achieved remarkable success, with eight approvals to date. siRNA therapeutics are short double-stranded RNAs designed to hybridize with complementary mRNA sequences and regulate disease-related protein expression through endogenous RNA interference (RNAi) mechanism. This manuscript outlines a framework of immunogenicity risk assessment for siRNA therapeutics, discusses the challenges associated with anti-drug antibody (ADA) assay development, and reviews available immunogenicity data from both approved and investigational GalNAc-siRNA therapeutics. Across clinical development programs, GalNAc- conjugated siRNA therapeutics have demonstrated a low immunogenicity risk profile, supported by comprehensive immunogenicity risk assessment and accumulated clinical data. Reported treatment-emergent ADA response has been generally low (≤ 6%), with no observed impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy and/or safety. Given the favorable immunogenicity profile observed to date, routine prospective ADA assessments throughout clinical development may not be scientifically warranted for all siRNA therapeutics. Instead, the manuscript advocates adopting a risk-based immunogenicity assessment strategy. This approach emphasizes immunogenicity risk assessment early in the program development, for low-risk molecules, such as GalNAc- or lipid-conjugated siRNA, ADA samples can be collected and banked during early phase studies for retrospective testing if evidence emerges of altered PK, PD, or immune-mediated adverse events. This risk-based immunogenicity assessment strategy ensures patient safety and therapeutic efficacy while streamlining development process for siRNA therapeutics.</p> Graphical Abstract <p></p>