ROMEO · Cracking the code on tumor targeting with nanostructures: competitive kinetics and extracellular vesicles

Today cancer remains a huge health concern, with around 20 million new cases and 10 million deaths per year worldwide. However, according to expectations, Nanomedicine should have ended cancer long time ago. The first nanomedicine (DoxilTM) a liposomal formulation based on the Enhanced Permeation and Retention (EPR) effect, dates from 1995. In the ensuing three decades, hundreds of anticancer nanoparticles with exciting properties were developed, but only a handful have reached the clinic, with rather limited effectiveness. Recent research has identified the root causes of the failure of Nanomedicine in cancer, which can be narrowed down to two problems: first, most nanoparticles (NPs) end up in the liver, trapped by Kupffer cells (KCs) in the slow-flow sinusoids; second, of the small fraction of NPs that escape KCs most fail at delivering therapy to tumor cells, ending up in off-target cells.ROMEO has been specifically conceived to address these problems and produce a therapeutic vector able to escape KCs, while guaranteeing a high tumor cell targeting capability. To achieve this, we will combine i) extracellular vesicles (EVs) as delivery vectors of high selectivity and ii) optimized NPs, as decoys able to saturate KCs uptake capacity. A novel approach, importing chemical engineering concepts (microfluidics, competitive adsorption/reaction kinetics) will provide actionable information to improve successive generations of EVs, NPs and feeding schemes in order to keep KCs saturated and maximize delivery to tumor cells. The solutions will be validated in a ground-breaking experimental design that circumvents previous problems of in vivo experiments. The final deliverable of ROMEO will be optimized EVs containing a therapeutic load, able to survive repeated sinusoid passes thanks to the optimal feeding of decoy NPs, and with a proven ability to target tumor cells. If successful, the main problem preventing the success of cancer nanomedicine will have been solved.