Anti-CD38 targeted nanotrojan horses stimulated by acoustic waves as therapeutic nanotools selectively against Burkitt’s lymphoma cells

The horizon of nanomedicine research is moving toward the design of therapeutic tools able to be completely safe per se, and simultaneously be capable of becoming toxic when externally activated by stimuli of diferent nature. Among all the stimuli, ultrasounds come to the fore as an innovative approach to produce cytotoxicity on demand in presence of NPs, without invasiveness, with high biosafety and low cost. In this context, zinc oxide nanoparticles (NPs) are among the most promising metal oxide materials for theranostic application due to their optical and semi-conductor properties, high surface reactivity, and their response to ultrasound irradiation. Here, ZnO nanocrystals constitute the stimuli-responsive core with a customized biomimicking lipidic shielding, resembling the composition of natural extracellular vesicles. This core–shell hybrid structure provides high bio- and hemocompatibility towards healthy cells and is here proofed for the treatment of Burkitt’s Lymphoma. This is a very common haematological tumor, typically found in children, for which consolidated therapies are so far the combination of chemo-therapy drugs and targeted immunotherapy. In this work, the proposed safe-by-design antiCD38-targeted hybrid nanosystem exhibits an efcient selectivity toward cancerous cells, and an on-demand activation, leading to a signifcant killing efcacy due to the synergistic interaction between US and targeted hybrid NPs. Interestingly, this innovative treatment does not signifcantly afect healthy B lymphocytes nor a negative control cancer cell line, a CD38- acute myeloid leukemia, being thus highly specifc and targeted. Diferent characterization and analyses confrmed indeed the efective formation of targeted hybrid ZnO NPs, their cellular internalization and the damages produced in Burkitt’s Lymphoma cells only with respect to the other cell lines. The presented work holds promises for future clinical applications, as well as translation to other tumor types.