**Erik Laurini, Domenico Marson \*, Suzana Aulic, Maurizio Fermeglia and Sabrina Pricl**

Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy

**\*** Correspondence: domenico.marson@dia.units.it; Tel.: +39-040-558-3750

Received: 21 June 2019; Accepted: 8 July 2019; Published: 10 July 2019

**Abstract:** In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing.

**Keywords:** RNAi therapeutics; siRNA delivery; amphiphilic dendrons; PAMAM dendrimers; self-assembling; nanovectors; gene silencing
