The present study describes the synthesis of chitosan-squalene (chitosan-SQ), a unique amphiphilic chitosan derivative, which enables the efficient formation of nanoparticles in acetate buffer by self-assembly. The influence of different parameters on the nanoparticle size such as percentage of substitution, pH of the acetate buffer, concentration in chitosan-SQ, and time of stirring was studied. It could be demonstrated that this new polymer was nontoxic to cells, biodegradable, and preserved the anti-infective properties of the initial chitosan.1 Moreover, chitosan-SQ showed good carrier properties by allowing the encapsulation of both hydrophilic and hydrophobic model drug compounds.