Thermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia

• DOI: 10.1126/sciadv.abm1418
• Publication Date: 2022-02-16T18:51:30Z
• Authors: Bo Hu; Bo Li; Kun Li; Yuanyuan Liu; Chunhui Li; Lulu Zheng; Mengjie Zhang; Tongren Yang; Shuai Guo; Xiyu Dong; Tian Zhang; Qing Liu; Abid Hussain; Yuhua Weng; Ling Peng; Yongxiang Zhao; Xing-Jie Liang; Yuanyu Huang
• Keywords: [CHIM.MATE] Chemical Sciences/Material chemistry; 0303 health sciences; 03 medical and health sciences; [SDV.CAN] Life Sciences [q-bio]/Cancer; Biomedicine and Life Sciences; [SDV.BIO] Life Sciences [q-bio]/Biotechnology; 3. Good health

Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a most challenging issue for siRNA drug development. Here, a series of ionizable lipid-like materials were rationally designed; 4 panels of lipid formulations were fabricated and evaluated on the basis of four representative structures. The lead lipid (A1-D1-5) was stable at 40°C, and the optimized formulation (iLAND) showed dose and time dual-dependent gene silencing pattern with median effective dose of 0.18 mg/kg. In addition, potent and durable reduction of serum cholesterol and triglyceride were achieved by administering siRNAs targeting angiopoietin-like 3 or apolipoprotein C3 ( APOC3 ) in high-fat diet–fed mice, db/db mice, and human APOC3 transgenic mice, respectively, accompanied by displaying ideal safety profiles. Therefore, siRNA@iLAND prepared with thermostable A1-D1-5 demonstrates substantial value for siRNA delivery, hyperlipidemia therapy, and prevention of subsequent metabolic diseases.