Antibiotic Nano-delivery Systems against Multidrug-resistant Bacteria: A Resistance Mechanism-to-Platform-to-Intervention Framework.

Abstract

Antimicrobial resistance arises from interacting processes operating at community, cellular, genetic, and regulatory levels, while treatment failure is further shaped by limited antibiotic access and exposure within complex infection environments. Antibiotic nano-delivery systems (ANDS) can address some of these barriers by altering drug protection, release, localization, intracellular exposure, and interactions with bacterial cells. Their effects, however, depend on the specific formulation: material class alone does not define biological function, and improved antibacterial efficacy after nanoencapsulation does not establish resistance reversal. This review develops a resistance mechanism-to-platform-to-intervention framework that links defined resistance-associated barriers to the formulation functions required to address them and to the evidence needed to support the corresponding therapeutic claims. This approach shifts evaluation from platform-centered ranking to formulation-level function and evidence. Across major ANDS platforms, the analysis shows that antibacterial and antibiofilm effects, resensitization, resistance reversal, and resistance prevention require different mechanistic and experimental evidence. Multimodal formulations are most informative when their individual functions address distinct coexisting barriers and their contributions are experimentally resolved. The review also identifies persistent translational constraints, including nanomaterial adaptation and co-selection, biosafety and pharmacokinetic uncertainty, manufacturing and regulatory requirements, and limited standardization of efficacy assessment. Progress toward clinical use will therefore depend on matching validated formulation functions to defined resistance contexts and integrating mechanism-specific and evolutionary endpoints with reproducible manufacturing and clinically relevant evaluation. STATEMENT OF SIGNIFICANCE: Antimicrobial resistance is sustained by interacting mechanisms that limit antibiotic access, exposure, and target engagement. Antibiotic nano-delivery systems (ANDS) can provide drug protection, controlled release, localization, co-delivery, and carrier-derived antibacterial functions, but nanoencapsulation alone does not establish resistance reversal. This review presents a resistance mechanism-to-platform-to-intervention framework that links seven resistance-associated pathways with six ANDS platform classes through formulation-specific functions and supporting evidence. It distinguishes antibacterial activity, antibiofilm activity, resensitization, resistance reversal, and resistance prevention. The review further examines nanomaterial adaptation, biosafety, pharmacokinetics, manufacturing, evidence standardization, clinical translation, and future development, providing a framework for selecting and evaluating ANDS against multidrug-resistant bacterial infections.