Surfactant-Engineered Niosomal Antibiotic Systems for Biofilm-Associated Infections: Design Principles and Translational Perspectives.

Persistent microbial biofilm infections remain a major obstacle to effective antimicrobial therapy due to restricted drug diffusion, metabolic heterogeneity, and the presence of tolerant bacterial subpopulations. In device-associated infections, biofilms substantially reduce antibiotic efficacy and contribute to chronic relapse despite adequate systemic exposure. Although nanocarrier-based delivery systems have been widely investigated, many formulations remain empirically developed with insufficient consideration of biofilm-specific physicochemical and biological barriers. This review examines surfactant-engineered niosomal antibiotic systems from a rational design perspective. Key formulation parameters, including surfactant type, hydrophile-lipophile balance (HLB), cholesterol content, surface charge, and microenvironment-responsive behavior, critically influence bilayer rigidity, permeability, encapsulation efficiency, intrabiofilm transport, and release kinetics. In particular, electrostatic interactions with the negatively charged extracellular polymeric substance (EPS) matrix and pH-responsive destabilization strategies are discussed as important determinants of localized antibiotic delivery within heterogeneous biofilm environments. Despite promising antibiofilm activity in vitro, translational progress remains limited by variability in formulation characterization, insufficient in vivo validation, and incomplete alignment between carrier responsiveness and biofilm microenvironmental conditions. By integrating insights from pharmaceutics, materials science, and microbial pathophysiology, this review proposes a structured framework for the rational design of surfactant-engineered niosomes and highlights key considerations for advancing antibiofilm nanomedicine.