Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo. 1. Background Despite important progress being made to treat different types of cancers, acquired resistance and some forms of aggressive or less frequent cancers are still waiting for efficient strategies. The new solutions proposed to solve these problems take into account the recent advances of our knowledge in general biology, and the biology of cancer in particular, but also relative solutions for a better distribution of the compounds in the patient's body, according to the type of cancer that needs to be treated. In the field of biology, the last two decades have seen the dawn of the epigenetic strategy [1,2]. If genetics are currently well understood by the scientific community, a question that remains for understanding why a genome common to all our cells (genotype) is able to produce different types of cells (phenotype). This question was solved by the observation that, for the same genome, only a< Leer menos