小干擾核糖核酸（siRNA）作為核苷酸類藥物，通過RNA干擾（RNAi）特異性誘導(dǎo)基因沉默而發(fā)揮作用，在代謝性疾病、抗感染及腫瘤等領(lǐng)域被廣泛應(yīng)用。目前已獲批上市4款基于N-乙酰半乳糖胺（GalNAc）偶聯(lián)技術(shù)siRNA藥物，匯總分析已上市GalNAc偶聯(lián)藥物的非臨床毒性特征及臨床不良反應(yīng)，初步明確非臨床研究中毒性常見類型，包括脫靶與非脫靶毒性等。結(jié)合GalNAc-siRNA類藥物非臨床研究實(shí)踐，了解可預(yù)測的脫靶毒性及對于非臨床安全性評價中的毒性關(guān)注點(diǎn)，以期為GalNAc-siRNA藥物臨床研究提供參考。

Small interfering RNA (siRNA), nucleotide drugs, are interfering with gene silencing specifically through RNA interference (RNAi) and have been widely applied in metabolic diseases, anti-infection and tumor indications. Currently, four siRNA drugs based on N-acetylgalactosamine (GalNAc) conjugated technology have been approved for market. In this paper, we summarized the non-clinical toxicity characteristics and clinical adverse reactions of approved GalNAc drugs, by clarifying the common types of toxicity in non-clinical studies identified, including off-target toxicity and non-off-target toxicity. Combined with the practice of non-clinical studies on GalNAc-siRNA drugs, the predictable off-target toxicity and toxicity concerns in non-clinical safety evaluation were understood to provide references for clinical trials.