Rational development of an mRNA antibody cocktail with extended therapeutic window against ricin intoxication

Ricin, a highly toxic protein derived from Ricinus communis, is recognized as a biological threat due to its high toxicity and the absence of approved specific antidotes. Monoclonal antibodies (mAbs) represent an emergency therapeutic for ricin intoxication. However, the short therapeutic window of existing antibody administration significantly limits their effectiveness in post-exposure treatment. To address these limitations, we developed a novel strategy leveraging lipid nanoparticle (LNP) encapsulated-mRNA platform for toxin antibodies delivery in vivo, enabling a time-saving, cost-effective approach that extends the therapeutic window. We designed and characterized two mRNA-encoded antibodies targeting the A chain (RTA) and B chain (RTB) of ricin, termed mRNA-43RCA and mRNA-Sy1H3, respectively. Then, each LNP-encapsulated mRNA antibody was combined to formulate the final mRNA antibody cocktail, termed mRNA-cocktail-LNP. In vivo studies demonstrated that a single administration of mRNA-cocktail-LNP enabled the rapid production of neutralizing antibodies, which conferred protection in mice against a subsequent lethal-dose ricin challenge. Additionally, mRNA-cocktail-LNP exhibited a significantly extended circulating half-life compared to its protein-format antibody in mice, and a single prophylactic dose provided complete protection against lethal ricin challenge for at least 14 days post administration. More importantly, mRNA-cocktail-LNP conferred protection even when administered 10 h after lethal-dose ricin exposure, demonstrating an extended therapeutic window. Taken together, our results indicate that mRNA-cocktail-LNP represents a promising therapeutic candidate against ricin intoxication, highlighting the potential of mRNA-LNP platform as a universal strategy for developing antibody-based countermeasures against ricin and a broad spectrum of other biological threats. KEY POINTS: • An mRNA antibody cocktail (mRNA-cocktail-LNP) was designed to against RT and protect the mice from challenge with ricin both prophylactic and post-exposure treatments • mRNA-cocktail-LNP with a prolonged half-life compared to its protein format. • mRNA-cocktail-LNP significantly extended the limited therapeutic window to 10 h for ricin intoxication treatment.