CRISPR-guided Cas9 and Cas12 proteins enable RNA-targeted DNA binding and/or cleavage, as well as several “CRISPR 2.0” applications, such as epigenetic, base, and prime editing. However, the most commonly used Cas proteins are relatively large in size, complicating in vivo delivery. Here, we describe a combination of structure-guided and AI-based protein engineering strategies to increase the gene editing functionalities of a miniature type V system in human cells. Moreover, we use metagenomic databases to detect related CRISPR systems, in order to test the scalability of our engineering efforts across orthologues. Finally, we test our most potent mini-nucleases and base editors in human iPSC-derived cardiomyocytes and in mouse embryos. In sum, we show a new pipeline for scalable CRISPR protein engineering and provide a suite of miniature Cas12 proteins for gene editing in human cells.