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From recombinant insulin to monoclonal antibodies, proteins have become essential drugs in the therapeutic arsenal and respond to a broad spectrum of diseases. While commercially available proteins have an extracellular activity, intracellular targets could be a powerful alternative to treat many pathologies such as cancers, immune disorders, but also infectious diseases. Nevertheless, to enter the cell and reach the target organelle or molecule, therapeutic proteins have to face numerous barriers (internalisation, endosomal escape, cytoplasm trafficking). In view of the fragile nature and high heterogeneity of proteins in term of size, charge and hydrophilic/lipophilic profile, the development of an efficient cytoplasm delivery system remains a long-standing challenge. The discovery of several gene editing tools (CRISPR-Cas9, TALEN, or other ZFP) has particularly boosted this research field in the last decade. Among delivery systems that can be used in vivo, some synthetic nanovectors offer interesting opportunities. In this review, we decided to describe the most recent progress in development of inorganic (silica, gold, phosphate, metal organic framework, carbon nanoparticles) as well as organic (polymer, lipid) nanoparticles both applied to intracellular protein delivery.

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