An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile
Résumé
Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treatvariousdiseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we reportan ionizable supramolecular dendrimervector,formed via self-assembly ofa small amphiphilic dendrimer, asan effective siRNA delivery system with favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has alow positively charged surface potential and nonotable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimerto enableformation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral, thus avoiding aggregation, nor too high, thus avoiding cytotoxicity, but was sufficient for favorable cellularuptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery systemeffectivelysilencedthe oncogenes Myc and Akt2with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications
Origine : Fichiers produits par l'(les) auteur(s)