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In 2019, a global pandemic evolved with currently more than 7 million deaths caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], leading to an unprecedented level of scientific research [2, 3]. SARS-CoV-2 belongs to the genus Betacoronavirus within the family of Coronaviridae (“coronavirus,” CoV) [2]. Previous betacoronaviruses, such as SARS-CoV and MERS-CoV, have crossed the species barrier, causing limited but severe epidemics [4], which illustrates the risk of future pandemics arising from emerging betacoronaviruses. 24 February 2025 Inhalation Point of view: The concept of an inhalable nanoparticle- based siRNA therapy for betacoronavirus infections Exploring the potential of RNA-based pulmonary nanotherapies for enhancing future pandemic preparedness Joschka T. Müller a , Thomas Michler, PD Dr. med. b and Olivia M. Merkel, Prof. Dr. rer. nat. a, c, d a Ludwig-Maximilians-University München b Institute of Laboratory Medicine, LMU University Hospital, LMU Munich c Center for NanoScience (CeNS), Munich d Cluster for Nucleic Acid Therapeutics Munich (CNATM) Introduction In 2019, a global pandemic evolved with currently more than 7 million deaths caused by the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) [1], leading to an unprecedented level of sci- entific research [2, 3]. SARS-CoV-2 belongs to the genus Betacoronavirus within the family of Corona- viridae ("coronavirus," CoV) [2]. Previous betacoro- naviruses, such as SARS-CoV and MERS-CoV, have crossed the species barrier, causing limited but severe epidemics [4], which illustrates the risk of future pandemics arising from emerging betacoronaviruses. erefore, prospectively, it seems to be of great rele- vance to develop a broad-spectrum therapy against betacoronaviruses. e purpose of this article is to provide insights into the rationale for a planned experimental approach to tackle betacoronaviruses via inhalable small interfering ribonucleic acid (siRNA) therapies. Table 1 and Figure 1 should serve as our compass throughout this article and resemble an experimental approach testing the efficacy of the formulation to be developed. While applying RNA interference (RNAi), siRNA is loaded into the RNA- induced silencing complex (RISC), which degrades mRNA [5]. Nearly all RNA Table 1 Key considerations for the development of an inhalable siRNA therapy against betacoronaviruses Factor Decision Rationale Active pharmaceutical ingredient (API) siRNA Adaptable, possible platform therapy, promising antiviral success Drug delivery system Polymer-based nanoparticles such as spermine-containing poly(β-amino) esters (PBAEs) Biodegradable, high encapsulation efficiency, coupling to targeting ligands possible, facilitating endosomal escape Route and mode of administration Pulmonary delivery via vibrating mesh nebulizer Direct application to site of action, no first-pass effect, high absorption rate, low nuclease activity, lower shear stress, nanoparticle formulations can be nebulized without loss of integrity or change of physicochemical parameters Advanced non-clinical testing approaches Air-liquid interface (ALI), Precision cut lung slices (PCLS) Sophisticated cell cultures models mimicking physiological circumstances in vivo, high throughput