Fig. 1: GMP iExoKras^G12D preclinical safety and biodistribution.

A Schematic representation of iExoKras^G12D GMP production. Conditioned media (CM) from mesenchymal stromal cells (MSC) cultured in GMP was centrifuged to remove debris, filtered through 0.2 μm filter, and ultracentrifuged. The exosomes pellet was resuspended, subjected to electroporation to incorporate siRNA targeting KRAS^G12D using a 1:1 ratio (by mass) of exosomal protein and siRNA, and evaluated using quality control (QC) analysis for size distribution (mean size <400 nm) and exosome surface detection of CD47 and CD63 by flow cytometry. B Representative picture of cryo-electron microscopy of GMP iExoKras^G12D. Scale bar: 100 nm. This experiment was performed once. C Schematic representation of a murine toxicology study using intravenous (i.v.) GMP iExoKras^G12D treatment (Rx) for three consecutive cycles. Each cycle represents two weeks (W1: week 1; W2: week 2, etc.) and three iExoKras^G12D treatments on days 1, 4, and 10. D Body weight measurements over time for the listed groups of mice, PT: pretreatment. 1X, 2X, and 4X exosomes reflect dosing corresponding to clinical trial dosing, see also Table 1, n = 10 mice per group. Data are presented as mean +/– SD. E Schematic representation of NHP toxicology study using intravenous (i.v.) GMP iExoKras^G12D treatment (Rx) for three consecutive cycles. Each cycle represents two weeks (W1: week 1; W2: week 2, etc.) and iExoKras^G12D treatments on the listed days, distributing three iExoKras^G12D treatments over the course of 2 weeks. F Body weight measurements over time for the listed NHP. For dosing details, see Table 1. G Schematic representation of NHP biodistribution study using intravenous (i.v.) or intraperitoneal (i.p.) GMP iExoKras^G12D that was labeled with PKH-67 or DiR dye. H, I Representative fluorescence images (H) of pancreas and liver sections from NHP following PKH-67⁺ iExoKras^G12D treatment and associated quantification (I) of the density of the ratio of PKH67 level over nuclear staining (DAPI) in the listed organs. Scale bar: 10 μm. This experiment was performed once. J Normalized relative luminescence unit (RLU) in the listed organs for the detection of DiR⁺ label following i.v. or i.p. DiR⁺ iExoKras^G12D treatment. CNS: central nervous system; GI: gastrointestinal; Med. oblongata: medulla oblongata; LN: lymph node. Data also presented in part in Supplementary Fig. 6B. Source data is provided as Source Data file.