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

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.