Thermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35171673.
- Also identified by DOI 10.1126/sciadv.abm1418 and PMC identifier 8849333.
- Licence recorded as CC BY-NC.
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Abstract
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 <i>angiopoietin-like 3</i> or <i>apolipoprotein C3</i> (<i>APOC3</i>) in high-fat diet-fed mice, db/db mice, and human <i>APOC3</i> 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.