Versatile fully biodegradable dendritic nanotherapeutics.

The repeated administration of non-degradable dendrimers can lead to toxicity due to their bioaccumulation. Furthermore, in drug delivery applications, carrier stability can result in low biological performance due to insufficient intracellular cargo release. A novel family of versatile, biosafe, water-soluble, and fully biodegradable PEG-dendritic nanosystems is proposed, which overcomes the limitations of the most used dendrimers. Their novelty relies on the full and adjustable degradability thanks to the presence of tunable ester bonds in every dendritic arm. These dendritic nanosystems present peripheral azides that allow their easy multivalent functionalization, by "click" chemistry, with a vast range of ligands to act as versatile carriers. Here, their amine-functionalization to serve as nucleic acid vectors for gene therapy is explored. These nanosystems complex and protect efficiently siRNA in very small dendriplexes (<60 nm), being successfully cell-internalized, including in hard-to-transfect neuronal cells even when in full tissue explants (dorsal root ganglia). Importantly, full biodegradability was crucial for an efficient nucleic acid intracellular release and the attainment of excellent transfection efficiencies. The reported fully biodegradable dendritic nanosystems can act as multi-function nanotherapeutics for gene therapy, and also for broader applications in nanomedicine. Therefore, they represent top-notch and clinically translatable health facilitating nanotechnologies for further developments in theranostics.