Background Preterm labor is the leading cause of infant mortality and morbidity worldwide, yet no pharmacological treatments currently exist to combat it. Although potentially effective therapies exist to suppress undesirable uterine contractions, these drugs often transport across the placental barrier, leading to adverse consequences on the developing fetus. Formulation strategies to limit fetal exposure may enable the safe and effective use of currently approved drugs for the prevention of preterm birth. Poly(lactic-co-glycolic) acid (PLGA) is a biocompatible copolymer that is used in a variety of drug formulations and in ‘dissolvable’ sutures. We hypothesize that optimally sized PLGA particles formulated with an anti-tocolytic will limit placental transport and suppress uterine contractions. Methods Therefore, we synthesized PLGA particles loaded with cargo and tested two formulations via an oil-in-water emulsion fabrication technique. One formulation used dichloromethane (DCM) with polyvinyl alcohol (PVA), and the other used ethyl acetate (EtAc) with D-α-tocopheryl polyethylene glycol succinate (Vitamin E-TPGS); both have been reported to successfully prepare PLGA particles in the target diameter range. Further studies to prove model translatability were performed, including kinetic release using two common tocolytics (indomethacin and nifedipine), in-vivo biodistribution, and ex-vivo experiments using murine uterine strips. Results The resulting EtAc/Vit E-TPGS emulsion produced average particle diameters of 1350 (± 64.5) nm (PDI: 0.3037). However, this formulation was more polydisperse compared to the DCM/PVA emulsion with average particle diameters of 1251 (±300.4) nm (PDI: 0.2020) that also exhibited acceptable day-to-day variability, ranging from 1137 to 1734 nm. We showed successful drug encapsulation in the absence of variation in particle size for indomethacin 1267 (± 82.72) nm and nifedipine 1142 (± 1.155) nm. Both tocolytics show the capacity for sustained release with total cumulative release of indomethacin (30 days) and nifedipine (24 days). In-vivo biodistribution studies demonstrate localization of the targeted PLGA particles to the uterus, and ex-vivo studies present a clear effect of the tocolytic drug after loading. Conclusion Through optimized physiochemical characteristics and clinical translation, this formulation has the potential to effectively inhibit preterm labor contractions in a novel delivery system. Next steps include decoration of particles with a uterine-selective antibody corona. The function of drug-loaded PLGA particles to inhibit uterine contractions will be tested in a model system with human tissue in organ baths. Results of these studies will be used to refine the drug to PLGA ratio and the PLGA characteristics to optimize efficacy and toxicity.