Innovative nanocarrier strategies: engineering biomaterials for enhanced treatment of infectious diseases

Antimicrobial-resistant biofilm infections remain difficult to eradicate because the biofilm matrix restricts antimicrobial penetration, creates physiologically heterogeneous bacterial subpopulations, and promotes persistence on wounds, implants, and indwelling devices. Stimuli-responsive biomaterials have been proposed to overcome these barriers by coupling local infection cues such as acidic pH, bacterial enzymes, reactive oxygen species, and redox imbalance or externally applied stimuli with targeted delivery, biofilm disruption, and controlled antimicrobial activity. Yet whether these systems solve the biofilm problem, rather than improve performance in simplified laboratory models, remains unresolved. This critical review evaluates how material architecture, stimulus selection strategy, cargo, and activation mechanism influence activity against antimicrobial-resistant biofilms. It compares responsive nanoparticles, nanozymes, antimicrobial peptide and enzyme-loaded systems, bacteriophage-enabled platforms, photothermal and photodynamic constructs. It emphasizes the relationship between claimed mechanisms and the biological relevance of the models used to test them, including mature versus early biofilms, mono- versus polymicrobial communities, clinically relevant fluid environments, infected tissue and implant models, and combination treatment with conventional antibiotics. The review assesses efficacy alongside the properties that determine translational readiness including selectivity for infected tissue, biodistribution and clearance, host toxicity and immunogenicity, reproducible synthesis, scale-up, sterilization, storage stability, and regulatory classification. The progress should not be judged by in vitro biofilm reduction alone, but by whether a platform produces a measurable therapeutic advantage in rigorous infection models without creating an unacceptable manufacturing or safety burden. By linking design features to model fidelity and translational constraints, this review identifies the evidence needed to distinguish genuinely clinically actionable nanobiomaterials from promising but premature antibiofilm concepts.