Computational Approaches in Improving Spermine-based RNA Nanocarriers

Olivia Merkel / Ludwig Maximilians University Munich, Germany

November 14, 2024, 2:30 - 3:30 pm CET

Online live talk


Delivery is the major hurdle thwarting the therapeutic potential of RNA medicines. While all siRNA drugs on the market target the liver, the lung offers a variety of currently undruggable targets which could be treated with RNA therapeutics. Hence, my lab rationally designs inhalable and biocompatible nanocarriers for efficient siRNA delivery to the lung.

Poly(beta-amino ester)s (Fig. 1) are biodegradable polymers capable of promoting nucleic acid delivery and can be tailormade to investigate structure–function relationships. We combine Design-of-Experiments (DoE) with Molecular Dynamics Simulations and Machine Learning (ML) to accelerate the discovery and optimization process of these siRNA nanocarriers.

Our previous results show the feasibility of synthesizing oleylamine-modified spermine-based poly(β-amino ester)s (PBAEs) that efficiently encapsulate siRNA into nanoparticles and the low polymer excess avoids problems of toxicity and polymer-induced side effects. The PBAE-based polyspermines successfully delivered siRNA for gene silencing in 2D cultures and Transwell® air-liquid-interface cultures. Additionally, Boc-protected PBAE-based polyspermines mediated therapeutic gene silencing of mutated KRAS resulting in impaired cell migration.

In an effort to compare polymer backbones, polyacrylamide (PAA)-based polyspermines were synthesized and resulted in more efficient siRNA delivery and gene silencing in Transwell® air-liquid-interface cultures compared with Lipofectamine but had a much more favorable safety profile in vitro and in vivo. After intratracheal administration to mice, the PAA-based polyplexes were efficiently taken up by Type II pneumocytes and successfully evaded recognition by macrophages in the lung.

Figure 1: A) Poly(β-amino ester)s (PBAEs) and B) synthesis of amphiphilic, spermine-based PBAEs by Michael addition polymerization and boc-deprotection with trifluoro acetic acid.

Olivia Merkel

has been a Professor of Drug Delivery at LMU Munich since 2015 and Chair since 2022. She is a Registered Pharmacist, received a MS (2006) and a PhD (2009) in Pharmaceutical Technology as well as numerous awards, including an ERC Starting Grant, ERC Proof-of-Concept Grant and ERC Consolidator Grant, the APV Research Award and the Carl-Wilhelm-Scheele-Award. Merkel is the author of over 100 articles and book chapters. She served as NIH reviewer from 2014-2015, SNF reviewer from 2018-2022, is an Editorial Board member for JCR, EJPB, Molecular Pharmaceutics and other journals, Associate Editor for DDTR and WIREs Nanomedicine and Nanobiotechnology, was the President of the German Controlled Release Society in 2020 and the Chair of the CRS Focus Group on Transdermal and Mucosal Delivery from 2020-2022, and currently is a scientific advisory board member of Coriolis Pharma, Carver Biosciences, AMW, and Corden Pharma as well as a co-founder of RNhale. Her research focuses mainly on RNA formulation and pulmonary delivery for the treatment of a variety of lung diseases.