SUMMARY This multidisciplinary proposal translates the efforts of a highly skilled group of researchers forging unprecedented pathways to promote hard and soft dental tissues preservation. Cutting-edge strategies inspired in approaches used in the medical field are employed to inhibit selectively endogenous metalloproteinases responsible for mediating the degradation of the collagen. In Dentistry, the destruction of this essential component of the extracellular matrix is strongly associated with the progression of periodontal disease and the breakdown of the dental substrate/restorative material interface leading to bacteria recolonization and recurrent caries, the primary cause of failure of dental restorations. These pathological conditions together are responsible for almost 80% of the tooth extractions in the United States. In order to address this serious public health issue, two innovative platforms are proposed. The first strategy is based on the encapsulation of two potent MMP inhibitors, the polyphenols quercetin and epigallocatechin gallate, in nano micelles cleavable by MMPs. The shell of the particles is composed of peptides with specific sequences of amino acids recognized and cleaved by the targeted MMPs, leading to rupture of the micelles and the release of the inhibitor molecules. In essence, this system enables the MMP to inhibit itself. The second strategy is an immunomodulatory platform based on the introduction of anti-MMP nanobodies, single domain antibodies derived from llama heavy-chain only antibodies, to inhibit/cease MMP proteolytic activity. As nanoparticles or nanobodies delivery vehicles, a dental primer formulation and a newly-designed multifunctional hydrogel are used for the adhesive interface and periodontal pockets, respectively. To validate the designed platforms, tooth-on-a-chip and animal models are being added in order to fast-track their translation into clinical care. The innovation of this proposal stems from: (1) the employment of a pioneering approach to inactivate MMPs in dental tissues based on enzymatic-responsive nanoparticles to deliver inhibitors, and (2) the introduction of a new paradigm based on the modulation of the MMPs activity by nanobody technology. After completing this project, we will have these two platforms tailored and validated to be delivered in vehicles compatible with the current clinical techniques employed to treat periodontitis and to hybridize the dentin during the restorative procedures, which will allow to bridge the gap between cutting-edge research and improved patient care. In addition, these platforms can be either combined or tailored in more complex and multi-functional entities and programmed to respond to a variety of enzymes and cytokines, which provides new opportunities to develop innovative dental tissue regeneration/preservation therapeutics to minimize tooth loss especially in highly vulnerable population.