CD45.2-PBD enables syngeneic HSCT and engraftment of autologous gene-edited HSCs with near-complete donor engraftment. (A) Schema for syngeneic HSCT of GFP-labeled B6 whole BM into B6 mice, using CD45.2-ADCs made with SAv-drug conjugates for conditioning. (B-C) Longitudinal peripheral blood donor chimerism overall and by lineage (B) and CBCs (C) in recipients conditioned with CD45.2-PNU, CD45.2-PBD, or their respective CD45.1-bound (isotype control) conjugates. Dotted lines in (C) are the lower reference limits for each CBC assay. (D) Schema for CRISPR-mediated disruption of GFP from B6-GFP HSPCs and transplantation of the edited HSPCs into B6-GFP mice. (E) Longitudinal peripheral blood donor chimerism overall and by lineage in CD45.2- or CD45.1-PBD conditioned B6-GFP mice receiving GFP-deleted HSPCs. For the populations of edited cells infused into these recipients, the average frequency of CD48⁻CD150⁺LSK cells that were GFP⁺ was 2.2% and 4.0% for CD45.2-PBD– and CD45.1-PBD–conditioned mice, respectively. Data points indicate mean ± SEM from mice accumulated over 2 independent experiments. Statistics: 2-way repeated-measures ANOVA (B,E). ∗∗∗∗P < .0001. BM, bone marrow; Cas9, CRISPR-associated protein 9; WBC, white blood cells.