The continuous emergence and spread of antibiotic-resistant bacteria are a global health emergency, debilitating the capability to prevent and cure various infectious diseases that were once treatable. Antibiotic therapy is further rendered ineffective due to biofilm formation and the ability of bacteria to thrive and colonize inside mammalian cells. Given the diminishing efficacy of available antibiotics combined with the scarcity of new therapeutics entering the antibiotic pipeline, innovative treatment strategies are urgently in demand. Nanomaterial-based strategies offer ‘outside of the box’ approach for the treatment of antibiotic-resistant bacterial infections. Nanomaterials feature tunable physicochemical properties that can be carefully modified to access multi-modal antimicrobial mechanisms novel to bacteria, allowing them to evade existing resistance mechanisms and have a higher barrier against resistance generation while maintaining high biocompatibility. This research focused on leveraging poly(oxanorborneneimide)-based polymeric nanoparticles to develop different antimicrobial therapies effective against difficult-to-treat resistant bacterial infections, including wound biofilms and bacteria-induced peritonitis. We fabricated different types of nanoparticles by varying their structural design and/or loading non-antibiotic therapeutics such as phytochemicals, siRNA or hydrophobic therapeutics. We then test these nanoparticles on in vitro and in vivo models to better understand their activity. Antibiotic-resistant wound biofilm infections are a major global healthcare challenge. Chapters 2 to 7 discuss how we utilized and developed cationic antimicrobial polymeric nanoparticles (PNPs) as topical therapeutics against wound biofilm infections. Our strategies include use of PNPs 1) in combination therapy with antibiotics, 2) integration with hydrogel materials, and 3) as a nanocarrier for other therapeutics to achieve multi-modal treatment. Intracellular pathogenic bacteria turn immune cells into a breeding ground for bacterial replication and reinfection, leading to challenging systemic infections including peritonitis. Chapters 8 and 9 focus on our strategy to address intracellular infections such as peritonitis using phytochemical-loaded polymeric nanoemulsions. The positively-charged polymer groups of the E-BNEs bind to the cell surface of macrophages, facilitating the entry of eugenol that then kills the intracellular bacteria. Through this work, we identified appropriate strategies that allow us to afford nanotherapeutics that can breach the biofilm, as well as selectively interact and kill bacteria. So far, we have demonstrated that nanotherapeutics can do what antibiotics cannot: penetrate and destroy biofilms, and effectively eliminate intracellular bacteria both in vitro and in vivo. All these while maintaining safety to our cells and without resistance development observed. Polymer nanotherapeutics offer a promising alternative to antibiotics, alleviating challenges faced in the post-antibiotic era.