Engineering controlled antimicrobial delivery across biofilm matrix barriers: mechanics, transport and nanocarrier...

Bacterial biofilms are a major challenge for antimicrobial therapy because they function not only as structured microbial communities, but also as complex biological barriers to drug delivery. Biofilm-associated bacteria are embedded within an extracellular polymeric substance (EPS) matrix that provides mechanical stability, regulates antimicrobial transport and generates heterogeneous microenvironments characterised by nutrient limitation, oxygen gradients and metabolically diverse bacterial subpopulations. As a result, therapeutic failure in mature biofilms often reflects a mismatch between antimicrobial activity and intra-biofilm delivery rather than insufficient drug potency alone. This review examines how EPS composition, architecture, viscoelasticity, molecular transport, physicochemical sequestration and bacterial physiology govern antimicrobial accessibility, local retention and therapeutic outcome. Matrix-remodelling strategies, including enzymatic degradation and quorum-sensing inhibition, are evaluated for their ability to weaken structural barriers and improve antimicrobial access. Building on these concepts, the review explores how nanocarrier-based delivery systems can be engineered to overcome transport limitations, optimise local therapeutic retention and control drug distribution within biofilms. Lipid-based, polymeric, inorganic, hybrid and stimuli-responsive platforms are critically considered in relation to particle size, surface charge, deformability, matrix affinity, controlled release, biodegradability and infection-site compatibility. Advanced experimental approaches, including confocal microscopy, rheological analysis, fluorescence recovery after photobleaching, single-particle tracking and microfluidic platforms, are discussed as tools for linking formulation design with biofilm transport behaviour. By reframing biofilm eradication as a coupled mechanics-transport-biology problem, this review establishes barrier-guided design principles for next-generation antibiofilm therapies that integrate matrix disruption, controlled antimicrobial transport and sustained bacterial killing.