Tyrosine-modified linear PEIs for highly efficacious and biocompatible siRNA delivery in vitro and in vivo

Therapeutic gene silencing by RNA interference relies on the safe and efficient in vivo delivery of small interfering RNAs (siRNAs). Polyethylenimines are among the most studied cationic polymers for gene delivery. For several reasons including superior tolerability, small linear PEIs would be preferable over branched PEIs, but they show poor siRNA complexation. Their chemical modification for siRNA formulation has not been extensively explored so far. We generated a set of small linear PEIs bearing tyrosine modifications (LPxY), leading to substantially enhanced siRNA delivery and knockdown efficacy in vitro in various cell lines, including hard-to-transfect cells. The tyrosine-modified linear 10 kDa PEI (LP10Y) is particularly powerful, associated with favorable physicochemical properties and very high biocompatibility. Systemically administered LP10Y/siRNA complexes reveal antitumor effects in mouse xenograft and patient-derived xenograft (PDX) models, and their direct application into the brain achieves therapeutic inhibition of orthotopic glioma xenografts. LP10Y is particularly interesting for therapeutic siRNA delivery. For therapeutic siRNA delivery, we generated and analyzed a set of small linear polyethylenimines bearing tyrosine modifications (LPxY). Substantially enhanced siRNA delivery and knockdown efficacy, favorable physicochemical nanoparticle properties, very high biocompatibility and therapeutic efficacy were observed in vitro and in different tumor models in vivo. [Display omitted] •Polyethylenimines (PEIs) are attractive systems for siRNA delivery in vitro/in vivo.•Here, a set of small linear PEIs bearing tyrosine modifications (LPxY) is explored.•LPxY show markedly enhanced transfection efficacy also in hard-to-transfect cells.•LPxY/siRNA complexes offer very favorable physical properties and biocompatibility.•Nanoparticle efficacies are seen in vitro, ex vivo and in three tumor models in vivo.