Herein, we report on the preparation of ultra-low sized (<100 nm in diameter) biodegradable polymeric capsules for potential applications as nanocontainers in antibiotic therapy. Hollow nanospheres based on the chitosan/poly(acrylic acid) pair are elaborated via (i) the layer-by-layer technique using gold nanoparticles (20 and 60 nm in size) as sacrificial templates, (ii) loading with amoxicillin, a betalactam antibiotic, and (iii) removal of the gold core via cyanide-assisted hydrolysis. Size, dispersity and concentration of the resulting nanocapsules are easily tuned by the nanoparticle templates, while wall thickness is controlled by the number of polyelectrolyte bilayers. Electrostatic interactions between the protonated amine groups of chitosan and the carboxyl groups of poly(acrylic acid) act as the driving attraction force allowing easy and fast design of robust and well-ordered multilayer films. Successful hydrolysis of the gold core is evidenced by time-dependent monitoring of the gold spectroscopic signature (absorbance at 519 nm and 539 nm for the gold nanoparticles with 20 and 60 nm, respectively). Crosslinked capsules are also prepared through crosslinking of the chitosan chains with glutaraldehyde. Chitosan-based nanocapsules are finally evidenced to be promising drug delivery vehicles of amoxicillin trihydrate with tuneable properties such as entrapment efficiency in the range of 62-75% and 3.5-5.5% concerning the drug loading. (C) 2018 Elsevier Inc. All rights reserved.