Background: The approval of anti-CD20 monoclonal antibody Rituximab more than 20 years ago opened a new class of highly effective immunotherapies for the treatment of B cell lymphomas. However, use of treatments that target only a single tumor antigen, such as CD20 or CD19, can apply selective pressure to tumors that results in loss or down-regulation of antigen expression in patients. To address this issue, Nutcracker Therapeutics has developed NTX-472, a nanoparticle formulated mRNA-based therapeutic candidate encoding a novel multispecific molecule that targets CD20 and CD19 as well as CD47, an innate immune checkpoint receptor upregulated by many tumors to evade immune surveillance. Methods: To understand the advantages gained from multispecific molecules for B cell lymphoma, we designed a panel of molecules targeting CD20, CD19 and CD47 and compared them to monospecific anti-CD20, Rituximab, or anti-CD19, Tafasitamab. A lead molecule was nominated based on in vitro tumor killing and B cell depletion assays, as well as on RBC binding. Efficacy of the lead molecule was evaluated in vivo as a nanoparticle formulated mRNA-based therapy (NTX-472) using Nutcracker Therapeutics’ Nutshell delivery platform. NTX-472 was evaluated in the Raji xenograft model for anti-tumor efficacy. Pharmacodynamics of intravenous administration of NTX-472 was assessed by measuring B cell depletion in cynomolgus macaques. Results: We identified a multispecific molecule that showed improved tumor killing and B cell depletion over mono and bispecific controls in vitro. In addition to the increased in vitro potency, our lead multispecific also demonstrated improved tumor specificity with preferential engagement of CD47 in presence of co-engagement of CD20 and CD19. Nutcracker Therapeutics’ Nutshell delivery platform enables in vivo production of mRNA-encoded complex biologics. Intravenous administration of NTX-472 in mice results in robust serum titers of our lead multispecific and control of Raji tumors in a xenograft model. To assess pharmacodynamics of NTX-472 in a relevant model, cynomolgus macaques were dosed intravenously with NTX-472, and protein expression and B cell depletion were measured in circulation. A single intravenous administration of NTX-472 results in rapid and durable depletion of B cells in circulation with no detectable multispecific binding to red blood cells. In addition, the in vivo expressed multispecific protein showed high purity both in mice and nonhuman primates. Conclusions: Here, we demonstrate the potency of NTX-472, a novel nanoparticle formulated mRNA therapeutic candidate encoding a multispecific protein targeting CD19, CD20, and CD47 that has increased specificity for tumor cells and has potential to enable broad efficacy while limiting hematotoxicity within a setting of increased tumor heterogeneity post-Rituximab treatment.