Engineered Supramolecular Therapeutics in Development for Combating Antibiotic-Resistant Bacterial Infections

The emergence of antibiotic-resistant bacteria has rendered conventional antibiotic treatments ineffective, necessitating the development of antibacterial agents with unique mechanisms of action. To address this challenge, researchers have increasingly resorted to synthetic and bioengineered nanomaterials to augment the antibacterial activity of nonantibiotic antibacterials (nonantibiotic antibacterial agents), including antimicrobial peptides (AMPs), metallic nanoparticles (MNPs), bacteriophages (phages), and phage derivatives such as endolysins, which are under extensive investigation. In this review, we discuss how modifications and syntheses of these agents, leveraging advancements in nanoscience and nanotechnology, have and can significantly enhance their antibacterial properties and overcome limitations such as cytotoxicity, instability, and poor bioavailability for in vivo or clinical use. Furthermore, we highlight supramolecular strategies for improved delivery, including phage-based, AMP-based, and endolysin-based systems and their demonstrated efficacy against persistent bacterial infections. Additionally, we highlight how the integration of artificial intelligence and machine learning ultimately promises to revolutionize the design, optimization, and clinical translation of these precision antimicrobials, paving the way for targeted and highly effective treatments.