This study investigated synthesis and characterisation of Nano-PLGA (poly(lactic-co-glycolic acid))/CO (clove-oil) nanoparticles. The delivery of drug-loaded nanoparticles to demineralised dentin substrates and their morphological association with a two-step etch-and-rinse adhesive system was studied. The effect of Nano-PLGA/CO pretreatment on micro-tensile bond strength of resin-dentin bonding was scrutinised. This study employed CO-containing PLGA nanoparticles as a delivery vehicle for sustainable drug release inside dentinal-tubules for potential dental applications. Emulsion evaporation resulted in uniformly distributed negatively-charged Nano-PLGA/Blank and Nano-PLGA/CO nanoparticles. Scanning electron microscopy/ transmission electron microscopy revealed even spherical nanoparticles with smooth texture. High CO-loading and encapsulation were achieved. Moreover, controlled CO-release was evidenced after 15 days, in-vitro and ex-vivo. Nanoparticles exhibited low initial toxicity towards human mesenchymal stem cells with excellent antibacterial properties. Nanoparticles penetration inside dentinal-tubules indicated a close correlation with resin-tags. Nano-PLGA/CO pretreatment indicated reduction in short-term bond strength of resin-dentin specimens. Nano-PLGA/CO as model drug-loaded nanoparticles showed excellent metric and antibacterial properties, low toxicity and sustained CO release. However, the loading of nanoparticles with CO up to approximate to 10mg (Nano-PLGA/CO:10) did not adversely affect short-term bond strength values. This drug-delivery strategy could be further expanded to deliver other pulp-sedative agents and medications with other dental relevance.