Nanoscale platforms for metronidazole delivery in infected tissue regeneration: From controlled release to smart systems

The failure of systemic antibiotics to resolve localized, biofilm-associated infections continues to stymie regenerative outcomes in bone, periodontal, and chronic wound repair. This has catalyzed a search for agents amenable to sophisticated local delivery. Here, we critically re-evaluate metronidazole (MTZ), a veteran antibiotic, arguing that its therapeutic role can be fundamentally reimagined through nanoscale engineering. We review the evolution of MTZ delivery systems, from simple fibers and hydrogels to smart, stimuli-responsive nanocarriers, which offer precise control over its release. These advanced systems not only overcome MTZ's inherent limitations by, for example, inducing localized hypoxia to broaden its activity against facultative anaerobes, but also unlock its latent therapeutic functions. Beyond its established role in infection control, this review confronts a central controversy in the literature that whether MTZ possess intrinsic regenerative properties or not. By consolidating disparate and often contradictory evidence, we establish a coherent model of a concentration-dependent, biphasic cellular response. We show that at nanomolar concentrations, MTZ directly promotes osteogenesis via the Wnt / β -catenin signaling pathway, whereas at the higher micro-to-millimolar concentrations required for antimicrobial efficacy, it significantly inhibits this process. This mechanistic dichotomy reveals a theranostic duality that necessitates a paradigm shift in platform design, moving towards two-phase or sequential release systems that can decouple antibacterial and pro-regenerative dosing. Ultimately, this review charts a course for the field, arguing that nanoscale engineering has elevated MTZ from a simple antimicrobial to a complex, multi-potent modulator of the tissue microenvironment. The imperative now shifts from incremental material fabrication to the strategic design and rigorous in vivo validation of intelligent systems capable of navigating MTZ's narrow therapeutic window to unlock its full regenerative potential.