抗心血管疾病的反义核酸药物研究进展

随着人们对疾病发病机制的理解,小核酸已成为治疗、干预疾病的一类越来越重要的药物。在传统的药物开发中,只有一小部分与人类疾病相关的靶点有相应的小分子或蛋白质药物。为了满足患者广泛的治疗需求,亟需针对传统药物不可成药靶点进行药物开发,而小核酸药物恰恰可以靶向原先不可成药的基因靶点。以反义寡核苷酸为代表的调节基因表达的核酸药物近年来得到加速发展,迄今为止,已经有多种反义寡核苷酸的上市药物,还有许多其他产品正在开发中。虽然绝大多数获批的药物适应症为罕见病,但目前多种处于中后期临床开发阶段的反义核酸药物的适应症为常见疾病,例如心血管疾病。得益于核酸化学技术的进步,目前的反义寡核苷酸药物与几十年前相比作用效力和安全性均有显著改善。本文综述了反义寡核苷酸药物的发展历史、作用机制和化学修饰技术,重点讨论了反义寡核苷酸药物在心血管疾病的开发和研究现状,为小核酸药物开发提供理论依据和技术参考。

Antitumor synergism between PAK4 silencing and immunogenic phototherapy of engineered extracellular vesicles

Immunotherapy has revolutionized the landscape of cancer treatment.However,single immunotherapy only works well in a small subset of patients.Combined immunotherapy with antitumor synergism holds considerable potential to boost the therapeutic outcome.Nevertheless,the synergistic,additive or antagonistic antitumor effects of combined immunotherapies have been rarely explored.Herein,we established a novel combined cancer treatment modality by synergizing p21-activated kinase 4(PAK4)silencing with immunogenic phototherapy in engineered extracellular vesicles(EVs)that were fabricated by coating M1 macrophage-derived EVs on the surface of the nano-complex cores assembled with si RNA against PAK4 and a photoactivatable polyethyleneimine.The engineered EVs induced potent PAK4 silencing and robust immunogenic phototherapy,thus contributing to effective antitumor effects in vitro and in vivo.Moreover,the antitumor synergism of the combined treatment was quantitatively determined by the Compu Syn method.The combination index(CI)and isobologram results confirmed that there was an antitumor synergism for the combined treatment.Furthermore,the dose reduction index(DRI)showed favorable dose reduction,revealing lower toxicity and higher biocompatibility of the engineered EVs.Collectively,the study presents a synergistically potentiated cancer treatment modality by combining PAK4 silencing with immunogenic phototherapy in engineered EVs,which is promising for boosting the therapeutic outcome of cancer immunotherapy.

Ionizable lipid-assisted efficient hepatic delivery of gene editing elements for oncotherapy

CRISPR/Cas9-based gene editing has emerged as a powerful biotechnological tool,that relies on Cas9 protein and single guided RNA(sgRNA)to edit target DNA.However,the lack of safe and efficient delivery carrier is one of the crucial factors restricting its clinical transformation.Here,we report an ionizable lipid nanoparticle(iLP181,pKa=6.43)based on iLY1809 lipid enabling robust gene editing in vitro and in vivo.The iLP181 effectively encapsulate psgPLK1,the best-performing plasmid expressing for both Cas9 protein and sgRNA targeting Polo-like kinase 1(PLK1).The iLP181/psgPLK1 nanoformulation showed uniformity in size,regular nanostructure and nearly neutral zeta potential at pH 7.4.The nanoformulation effectively triggered editing of PLK1 gene with more than 30%efficiency in HepG2-Luc cells.iLP181/psgPLK1 significantly accumulated in the tumor for more than 5 days after a single intravenous injection.In addition,it also achieved excellent tumor growth suppression compared to other nucleic acid modalities such as siRNA,without inducing adverse effects to the main organs including the liver and kidneys.This study not only provides a clinically-applicable lipid nanocarrier for delivering CRISPR/Cas system(even other bioactive molecules),but also constitutes a potential cancer treatment regimen base on DNA editing of oncogenes.