Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. While some current CVD-focused CRISPR approaches, such as PCSK9 or TTR knockout in the liver, are highly efficient, there is a lack of strategies that directly aim at editing heart cells in situ. Partially, this challenge arises from the absence of scalable and translationally relevant in vitro model systems for evaluating CRISPR delivery and editing techniques. In this study, we demonstrate that engineered human iPSC-derived heart organoids, referred to as epicardioids, serve as a viable platform for assessing LNP/mRNA delivery of CRISPR systems and conducting heart cell-specific gene editing within a human multi-cellular context. Epicardioids accurately mimic the morphological and functional characteristics of the ventricular wall, offering a pulsating, intricate 3D in vitro representation of the human heart. We show LNP-based delivery of mRNA specifically into the outer, epicardial layer of cardiac organoids and highlight strategies to rapidly test different LNP formulations, modified mRNAs, and CRISPR modalities in this scalable 3D system in vitro.