Professor Koen Raemdonck, Ghent Research Group on Nanomedicines, Faculty of Pharmaceutical Sciences, Ghent University, Belgium

Small molecules and peptides to promote delivery of RNA therapeutics

RNA drugs are an emerging class of therapeutics that address diseases at the genomic and/or transcriptomic level. This presentation describes strategies based on the repurposing of existing drugs and bio-inspired peptides to enable safe and effective RNA delivery.

Despite their therapeutic promise, widespread clinical translation of RNA drugs is hampered by many extra- and intracellular barriers, requiring formulation in polymer- or lipid-based nanocarriers. However, typically only a fraction of the RNA cargo internalized by target cells escapes into the cytosol. We recently reported on the repurposing of widely applied cationic amphiphilic drugs (CADs) as RNA delivery enhancers. Due to their physicochemical properties, CADs passively accumulate in the (endo)lysosomal compartment causing a transient permeabilization of the lysosomal membrane, facilitating cytosolic drug delivery. In addition, we also demonstrate that this strategy can be exploited to improve cancer cell killing, e.g. in combination with light. Moreover, integrating CADs into lipid nanoparticles (LNPs) and polyion complex micelles was shown to modulate their RNA delivery performance [1-4]. Finally, this talk describes the repurposing of small cationic amphiphilic peptides, including peptides derived from endogenous biomaterials such as pulmonary surfactant, to promote intracellular RNA delivery via inducing endosomal membrane fusion [5]. Potential therapeutic applications that will be discussed in the presentation include local therapy (e.g., cornea, lung) as well as selected applications in oncology.

Improving nanocarrier-mediated cytosolic delivery with existing drugs or bio-inspired materials can be considered as an important dose-sparing strategy, enabling safer application of RNA therapeutics.

Figure 1. Integration of cationic amphiphilic drugs (CADs) into LNPs modulates their in vitro and in vivo performance. Image taken from ref [3]. Copyright © 2024 American Chemical Society.

[1] Van de Vyver et al., ACS Nano 2020, 14:4774-4791.
[2] Bogaert et al., J. Controlled Release 2022, 350: 256-270
[3] Bogaert et al., Nano Lett. 2024, 24:2961-2971.
[4] Schneider et al., Adv Mat. 2024, 36:e2404784.
[5] Guagliardo et al., ACS Nano 2021, 5:8095-8109.