Phenylketonuria (PKU) is the most common genetic enzyme defect, with an overall incidence in Europe and the USA of 1:10,000-20,000 live births per year. Patients suffer from a genetic defect in the liver enzyme phenylalanine hydroxylase (PAH), which normally metabolizes the amino acid phenylalanine (Phe) into the amino acid tyrosine. This specific enzyme defect, which results in an increase in the level of systemic Phe in the first few years of life, can lead to severe mental retardation. Herein we propose a research project in which we will further develop the sub-compartmentalized assembly named capsosomes, which consist of polymer capsules assembled by the layer-by-layer (LbL) technique containing intact liposomes, as an oral-delivered artificial cell for enzyme replacement therapy with the aim to provide a solution for the most common inborn disease: phenylketonuria. In particular, I will (i) substantially improve the actual capsosome assembly by constructing the polymer shell in a single step using poly-dopamine (PDA), (ii) encapsulate the PAL enzyme into the liposomal sub-compartments and perform the conversion of Phe into trans-cinnamic acid, (iii) study the preservation of the PAL activity for oral administration by exposing the enzyme-loaded capsosomes to different environments which mimic the stomach and the intestine track, (iv) design of liposomes which are pH-sensitive in alkali media by two different strategies in order to obtain liposomes with enhanced permeability at intestine physiological conditions and, finally (v) synthesize thiol-modified PDA (PDASH) with the aim to obtain biodegradable capsosomes at intestine physiological concentrations of glutathione (GSH).