Endogenous and exogenous stimuli-responsive nanocarriers for targeted and controlled therapy of diabetic foot ulcers: Design strategies, therapeutic applications and translational perspectives

Diabetic foot ulcers (DFUs) are severe complications of diabetes mellitus characterized by chronic inflammation, persistent infection, oxidative stress, impaired angiogenesis, hypoxia, and delayed tissue repair. The complex and heterogeneous wound microenvironment presents major challenges for conventional drug-delivery approaches, including inadequate drug retention, premature degradation, poor tissue penetration, and off-target exposure. Stimuli-responsive nanocarriers have emerged as promising platforms for addressing these limitations by enabling localized, controlled, and temporally regulated therapeutic delivery in response to disease-associated or externally applied stimuli. This review provides a comprehensive analysis of endogenous and exogenous stimuli-responsive nanocarriers for targeted DFU management. It places particular emphasis on pathological cues in the diabetic wound microenvironment, including pH, reactive oxygen species (ROS), glucose, enzymes, hypoxia, and bacterial biofilms, and how to exploit them for rational nanocarrier design. Exogenous triggers, including light, ultrasound, magnetic fields, and electrical stimulation, are also discussed with respect to their mechanisms, therapeutic applications, advantages, and limitations. The review further examines single, dual, and multi-stimuli-responsive systems, therapeutic cargoes, nanocarrier architectures, wound-dressing and scaffold integration, and their effects on drug release, antibacterial activity, oxidative-stress modulation, angiogenesis, and wound closure. Selected multifunctional systems incorporating imaging or biosensing capabilities are discussed as emerging theranostic platforms. In addition, comparative therapeutic benchmarking and critical translational considerations, including scalability, batch-to-batch reproducibility, sterilization, stability, quality-by-design, GMP manufacturing, regulatory requirements, and clinical translation, are evaluated. Overall, stimuli-responsive nanocarriers represent a promising strategy for achieving microenvironment-responsive and targeted therapy of DFUs, although further standardization, safety evaluation, and clinical validation are required to establish their therapeutic potential.