Abstract The development of microbial resistance to antimicrobial agents is one of the biggest public health issues of the 21st century. Antibiotic-resistant bacteria (ARB) cause more than 2.8 million antibiotic-resistant infections in the U.S. each year, and more than 35,000 people die as a result. The principal ways of antibiotic resistance development are related to the intrinsic bacteria’s ability to evolve rapidly through mutations to either modify these targets or the pathways for their synthesis, alter or degrade the antibiotic, or pump the antibiotic out of the cell. Moreover, of critical importance is that all of these resistance mechanisms are encoded by antibiotic resistance genes (ARGs), which are stable molecules encoded in the DNA and can be passed to daughter cells or transported by horizontal gene transfer to neighboring pathogens. Despite tremendous efforts utilizing a wide range of antibiotic discovery platform strategies, their success has been at best incremental. Therefore, there is a critical need to develop effective approaches to simultaneously eliminate both ARB and ARGs. Recently, the use of nanomaterials with antimicrobial activity has been explored as a new alternative against ARB and ARGs. Silver nanoparticles (AgNPs) have been reported to have myriad applications as antimicrobial agents. In addition, photodynamic inactivation (PDI) is also a feasible strategy to eliminate ARB and ARGs. The remarkable features of AgNPs such as large surface area, capability to carry and release Ag+ ions, and ability to modulate the microbial influx/efflux pumps; and PDI like efficient generation of ROS and the fact that does not generate further resistance make these treatment modalities a promising alternative for the inactivation of ARB and ARGs. We hypothesize that by combining both approaches, PDI and AgNPs, in the same platform a synergistic effect to eliminate ARB and destroy ARGs will be achieved. The main goal of this project is to develop a light-activated silver nanoparticulate system for the effective treatment of ARB and ARGs. This project consists of three aims: in Aim 1, we will synthesize and characterize protoporphyrin IX (PpIX)-loaded AgNPs. This aim will demonstrate that fabricating a rationally designed AgNP platform will enable a large payload of PpIX to be carried in a stable formulation with tunable surface properties. For Aim 2, we will investigate the chemical and colloidal stability of PpIX-AgNP materials under different culture medium and light irradiation conditions. This aim will provide key information for the optimization of the platform and the influence of the environment on the generation of ROS and Ag+ ions. Finally, in Aim 3, we will study the antimicrobial efficacy of PpIX-AgNPs against a panel of ARB, the ARGs degradation kinetics and the nanoparticles cytotoxicity in mammalian cells. The information obtained in this aim will allow us to move forward this platform to therapeutic applications.