Abstract
Antimicrobial resistance continues to rise globally, with biofilm-associated infections intensifying the clinical burden through persistent tolerance to antibiotics and evasion of immune responses. Biofilms, structured microbial communities embedded in a protective extracellular matrix, underlie many chronic and recurrent infections, including endocarditis, urinary tract infections, cystic fibrosis lung disease, and device-related infections. Conventional antibiotics often fail in these contexts, and the discovery pipeline for novel agents remains limited. Nanotechnology has therefore emerged as a promising alternative, offering unique physicochemical features that enable enhanced penetration into biofilm matrices, improved drug stability, and targeted delivery of therapeutic agents. Diverse nanosystems, including metallic, polymeric, lipid-based, and ligand-functionalized platforms, have shown encouraging results in vitro and in vivo, demonstrating superior biofilm disruption and bacterial eradication compared with conventional therapies. Nevertheless, translating these advances into clinical practice remains challenging. Key barriers include complex and costly synthesis, scalability under good manufacturing practices, limited drug loading efficiencies, variability of preclinical biofilm models, regulatory uncertainties, and the risks of nanoparticle (NP)-induced toxicity, unpredictable biodistribution, and potential resistance development. Moreover, the dynamic interactions between NPs, host fluids, and biofilm extracellular matrices complicate pharmacokinetic and pharmacodynamic predictability. Addressing these obstacles requires coordinated efforts to refine manufacturing processes, standardize biofilm models, and implement nanospecific regulatory frameworks. With careful optimization, nanomedicine holds the potential to redefine the therapeutic landscape for biofilm-related infections.