A general methodology was proposed to prepare highly functionalized poly(alkyl cyanoacrylate) nanoparticles by means of Huisgen 1,3-dipolar cyclo-addition, the so-called click chemistry. To achieve this goal, different protocols were investigated to obtain azidopoly(ethylene glycol) cyanoacetate of variable molar mass, followed by a Knoevenagel condensation-Michael addition reaction with hexadecyl cyanoacetate to produce a poly[(hexadecyl cyanoacrylate)-co-azidopoly(ethylene glycol) cyanoacrylate] (P(HDCA-co-N(3)PEGCA)) copolymer, displaying azide functionalities at the extremity of the PEG chains. As a proof of concept, model alkynes were quantitatively coupled either to the P(HDCA-co-N3PEGCA) copolymers in homogeneous medium followed by self-assembly in aqueous solution or directly at the surface of the preformed P(HDCA-co-N3PEGCA) nanoparticles in aqueous dispersed medium, both yielding highly functionalized nanoparticles. This versatile approach, using alkyl cyanoacrylate derivatives, opened the door to ligand-functionalized and biodegradable nanoparticles with "stealth" properties for biomedical applications.