**Sandra Noske, Michael Karimov, Achim Aigner \* and Alexander Ewe \***

Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany; Sandra.noske@medizin.uni-leipzig.de (S.N.); michael.karimov@medizin.uni-leipzig.de (M.K.)

**\*** Correspondence: achim.aigner@medizin.uni-leipzig.de (A.A.); alexander.ewe@medizin.uni-leipzig.de (A.E.); Tel.: +49-(0)341-9724660 (A.A.)

Received: 12 August 2020; Accepted: 7 September 2020; Published: 10 September 2020

**Abstract:** The delivery of small interfering RNAs (siRNA) is an efficient method for gene silencing through the induction of RNA interference (RNAi). It critically relies, however, on efficient vehicles for siRNA formulation, for transfection in vitro as well as for their potential use in vivo. While polyethylenimines (PEIs) are among the most studied cationic polymers for nucleic acid delivery including small RNA molecules, polypropylenimines (PPIs) have been explored to a lesser extent. Previous studies have shown the benefit of the modification of small PEIs by tyrosine grafting which are featured in this paper. Additionally, we have now extended this approach towards PPIs, presenting tyrosine-modified PPIs (named PPI-Y) for the first time. In this study, we describe the marked improvement of PPI upon its tyrosine modification, leading to enhanced siRNA complexation, complex stability, siRNA delivery, knockdown efficacy and biocompatibility. Results of PPI-Y/siRNA complexes are also compared with data based on tyrosine-modified linear or branched PEIs (LPxY or PxY). Taken together, this establishes tyrosine-modified PPIs or PEIs as particularly promising polymeric systems for siRNA formulation and delivery.

**Keywords:** polypropylenimine dendrimers; polyethylenimines; tyrosine-modified polypropylene-imines; tyrosine-modified polyethlyenimines; PPI-Y; siRNA transfection; polymeric nanoparticles
