Advancements to gene therapy and gene editing technologies necessitate strong understanding of delivery or editing outcomes on a single-cell level. To evaluate the biodistribution of stem cell (HSC)-derived adeno-associated viral (AAV) vectors we utilized cre-dependent Ai14 (tdTomato) reporter mice. Upon investigation we identify several capsids that confer a high degree of HSC transduction surpassing the current standard serotype. These data provide insight into novel capsids that efficiently transduce HSCs without requiring detrimental ex vivo manipulation. We next cross and utilize Ai14 (tdTomato)/Ai6 (zsGreen) mice to better understand editing outcomes after using CRISPR/Cas9 technology for large deletions (CRISPR-del). Clinical application of CRISPR-del is inefficient, and methods to improve utility suffer from our inability to rapidly assess mono- vs. biallelic deletions. Here, we establish a model system for investigating allelic heterogeneity (Ai14/Ai6) at the single-cell level and identify indel scarring from non-simultaneous nuclease activity at gRNA cut sites as a major barrier to CRISPR-del efficacy. We show that non-simultaneous nuclease activity is partially circumvented via restriction of CRISPR/Cas9 expression using inducible AAVs (Xon) or lipid nanoparticles (LNPs). We next utilize chemical inhibitors and siRNAs to investigate the effect of impaired DNA repair on CRISPR-del frequency and observe significant improvements upon inhibition of non-homologous end joining. These data will inform therapeutic approaches for phenotypes that require either large mono- or biallelic deletions. Finally, we utilize our inducible Xon system to investigate differences in immunogenicity to transgenes when finely controlling AAV expression. Here, we observe a series of tolerization events to SaCas9, suggesting that inducible AAV expression of transgenes are a safer alternative in lieu of constitutive expression.