Stimuli-responsive nanocarriers for precision targeted and controlled antimicrobial drug delivery in drug-resistant...

Antimicrobial resistance (AMR) represents a critical and escalating threat to global health, driven not only by microbial evolution but also by fundamental limitations in the pharmacokinetic and spatial delivery of antimicrobial agents in vivo. Conventional antibiotics exhibit non-specific systemic distribution, frequently fail to achieve sustained therapeutic concentrations at infection sites, and expose both pathogenic and commensal microbiota to sub-inhibitory levels that accelerate resistance selection. In contrast, infected tissues exhibit distinct and dynamic microenvironmental features-including acidic pH, elevated reactive oxygen species, pathogen-associated enzymatic activity, hypoxia, and localized inflammatory signaling-that are largely absent in healthy tissues and provide exploitable triggers for targeted therapy. Stimuli-responsive nanocarriers are engineered to sense and respond to these pathological cues, enabling spatiotemporally controlled and infection-specific drug release while minimizing systemic exposure. In this review, we systematically analyze the mechanistic foundations of pH-, enzyme-, redox-, and multi-stimuli-responsive nanocarriers, with particular emphasis on how trigger-induced physicochemical transformations govern drug retention, activation, penetration, and release within drug-resistant infection niches. We further examine how these platforms address key resistance-associated barriers, including impaired tissue penetration, biofilm-associated tolerance, intracellular pathogen persistence, efflux-mediated drug extrusion, and enzymatic antibiotic degradation. Importantly, we provide a critical comparison between passive nanocarriers, stimuli-responsive systems, and free antibiotics, highlighting the conditions under which infection-synchronized delivery enhances antimicrobial efficacy, reduces off-target toxicity, and mitigates resistance-selective pressure. We also evaluate current translational challenges, including microenvironmental heterogeneity, trigger variability, long-term safety, scalable manufacturing, and regulatory complexity. Collectively, stimuli-responsive nanocarriers represent a paradigm shift from passive systemic exposure toward context-aware, site-selective antimicrobial intervention, offering a promising strategy to overcome persistent limitations in anti-infective therapy and address AMR beyond the pace of conventional antibiotic discovery.