Quo vadis? – Visualizing the tropism of tumor-derived cellular nanovesicles

Small extracellular vesicles (sEVs) and nanovesicles (NVs) derived from tumor cells hold great potential for targeted drug delivery due to their inherent tumor-homing properties. This study aimed to comparatively evaluate the physicochemical characteristics, cellular uptake, pharmacokinetics, tumor accumulation, and biodistribution of sEVs and NVs derived from two different cancer cell lines. sEVs and NVs were isolated from human metastatic breast cancer (MDA231) and pancreatic cancer (8988t) cells, respectively, and then characterized, further labeled with PbS quantum dots (QDs) or PKH26 dye. Cellular uptake of sEVs from different parental cells was examined by MDA231 cells in vitro, and in vivo biodistribution and pharmacokinetics of different sEVs and NVs were assessed in MDA231 cell-xenografted mouse models, tracked under fluorescence imaging in the visible or near-infrared (NIR) II region. Having comparable particle sizes and surface charges, MDA231-derived sEVs exhibited preferential uptake by MDA231 cells compared with sEVs derived from 8988t cells. In contrast, NVs showed a higher level of CD9 tetraspanin inheritance than sEVs when normalized to the total protein input of the same parental cell. In vivo fluorescence imaging revealed similar circulation half-lives of approximately 4–5 h for both MDA231- and 8988t-derived sEVs and NVs. PbS QD labeling provided stronger and more stable fluorescence signals than PKH26 dye. MDA231-derived sEVs or NVs showed higher accumulation in MDA231 tumor-bearing mice than their counterparts originating from 8988t cells. Tumor-derived sEVs and NVs exhibit favorable pharmacokinetic profiles and enhanced accumulation in homologous tumors, underscoring their promise as targeted delivery platforms for cancer therapy.