The controlled delivery of antibiotics, anti-inflammatory agents, or chemotherapeutic agents to the periodontal site is a recognized strategy to improve the efficiency of regenerative processes of hard tissues. A novel approach based on the trapping of tetracycline hydrochloride-loaded particles in polycaprolactone nanofibers was used to guide the regeneration processes of periodontal tissue at the gum interface. Chitosan nanoparticles loaded with different levels of tetracycline hydrochloride (up to 5% wt) were prepared by solution nebulization induced by electrical forces (i.e. electrospraying). The fine tuning of process parameters allows to obtain nanoparticles with tailored sizes ranging from 0.485 ± 0.147 µm to 0.639 ± 0.154 µm. The tetracycline hydrochloride release profile had a predominant burst effect for the first 70% of release followed by a relatively slow release over 24 h, which is promising for oral drug delivery. We also demonstrated that trapping tetracycline hydrochloride-loaded particles with submicrometer diameters into a polycaprolactone fiber network contributed to slowing the release of tetracycline hydrochloride from the nanoparticles, thus providing a more prolonged release in the periodontal pocket during clinical therapy. Preliminary studies on human mesenchymal stem cells confirm the viability of cells up to 5 days after culture, and thereby, validate the use of nanoparticle-/nanofiber-integrated systems in periodontal therapies.