Effective cytocompatible nanovectors based on serine-derived gemini surfactants and monoolein for small interfering RNA delivery

Supplementary data to this article can be found online athttps://doi.org/10.1016/j.jcis.2020.09.077.

Non-viral gene therapy based on gene silencing with small interfering RNA (siRNA) has attracted great interest over recent years. Among various types of cationic complexation agents, amino acid-based surfactants have been recently explored for nucleic acid delivery due to their low toxicity and high biocompatibility. Monoolein (MO), in turn, has been used as helper lipid in liposomal systems due to its ability to form inverted nonbilayer structures that enhance fusogenicity, thus contributing to higher transfection efficiency. In this work, we focused on the development of nanovectors for siRNA delivery based on three gemini amino acid-based surfactants derived from serine (12Ser)2N12, amine derivative; (12Ser)2COO12, ester derivative; and (12Ser)2CON12, amide derivative individually combined with MO as helper lipid. The inclusion of MO in the cationic surfactant system influences the morphology and size of the mixed aggregates. Furthermore, the gemini surfactant:MO systems showed the ability to efficiently complex siRNA, forming stable lipoplexes, in some cases clearly depending on the MO content, without inducing significant levels of cytotoxicity. High levels of gene silencing were achieved in comparison with a commercially available standard indicating that these gemini:MO systems are promising candidates as lipofection vectors for RNA interference (RNAi)-based therapies.

The authors acknowledge Fundação para a Ciência e a Tecnolo-gia (FCT) for financial support through projects UIDB/00081/2020 and UIDB/50006/2020. This work was supported by the‘‘Contrato-Programa” UIDB/04050/2020 funded by national fundsthrough the FCT I.P. Dr. Marisa Passos is gratefully acknowledged for help with the statistical analysis of cytotoxicity data. Fundingby the CCDR-N/NORTE2020/Portugal2020 through project DESign-BIOtechHealth (ref. Norte-01-0145-FEDER-000024) is also acknowledged. I. S. Oliveira and S.G. Silva also acknowledge finan-cial support from FCT through PhD grant SFRH/BD/108629/2015 and Individual Call to Scientific Employment Stimulus - CEEC Indi-vidual grant CEECIND/01932/2017, respectively

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