Neurological disorders, a leading global cause of death, include conditions that affect various parts of the nervous system. A major challenge in these disorders is the limited ability of axons to regenerate, which is associated with inhibitory proteins such as PTEN [1]. RNA-based therapeutics, especially siRNAs, have the potential to silence these inhibitory pathways, but their clinical use is hindered by poor stability and cellular uptake [2]. These drawbacks can be surpassed by using safe and efficient delivery vectors with the capacity to complex and protect naked siRNA [2]. 

Cationic dendrimers are promising carriers for this and other nucleic acids due to their capacity to complex them in compact nanostructures (“dendriplexes”), protecting them from endonuclease degradation and rapid renal clearance, and favoring cellular uptake [3]. However, the repeated administration of non-degradable synthetic materials can lead to toxicity due to their bioaccumulation. Furthermore, in gene therapy applications, carrier stability can result in low transfection efficiencies due to insufficient intracellular nucleic acid release. Due to this, we have proposed a novel family of versatile, biosafe, water-soluble, and fully biodegradable PEG-dendritic nanosystems, which present peripheral azides that allow their easy multivalent functionalization, by “click” chemistry, with a vast range of ligands to act as versatile carriers [4, 5]. Here, their amine-functionalization to serve as nucleic acid (siRNA) vectors for gene therapy was explored. Moreover, after neuro-targeting of the corresponding (antiPTEN)siRNA-dendriplexes, an enhanced selective neuronal targeting and internalization were confirmed. These dendriplexes maintain biocompatibility and efficient siRNA delivery in neuronal cultures as well as a significantly enhance axonal growth [6]. 

The reported fully biodegradable dendritic nanosystems can act as multi-function nanotherapeutics for gene therapy, and also for broader applications in nanomedicine.

References 
[1] K.K. Park, et al. Science (2008) 322, 963-966. 
[2] R.L. Setten, et al. The current state and future directions of RNAi-based therapeutics, Nat. Rev. Drug Discov. (2019) 18, 421–446. 
[3] A.P. Spencer, et al, et al. Biomaterials Science (2023), 11, 1499-1516. 
[4] A.P. Pêgo, V. Leiro, and co-inventors. Biodegradable Dendritic Structure, Methods and Uses Thereof. WO2017203437, 2017. (US10858484B2, 2020). 
[5] Leiro, V., Spencer, A.P., Magalhães, N., Pêgo, A.P. Biomaterials (2022) 281:121356. DOI: 10.1016/j.biomaterials.2021.121356. 
[6] A.P. Spencer, et al. BioRxiv: The preprint server for biology. (2024). DOI: https://doi.org/10.1101/2024.09.05.611457.