STIMULI-RESPONSIVE NANOCARRIERS FOR TARGETED DRUG DELIVERY: FROM FUNDAMENTAL MECHANISMS TO CLINICAL TRANSLATION

Conventional pharmacotherapy often faces limitations such as low aqueous solubility, non-specific biodistribution, rapid clearance, and systemic toxicity, which limit the availability of active agents at the target site. In the last two decades, stimuli-responsive nanocarriers have emerged as a promising solution, nanoscale drug delivery mechanisms with molecular switches that can respond to certain biochemical or physical characteristics of the diseased microenvironment to trigger targeted drug release. This review compiles the existing knowledge of these systems, classifying them according to the triggering signal type and summarizing their design logic, chemistry, and performance. The endogenous (internal) triggers discussed are pH gradients, redox state imbalances, and overexpression of degradative enzymes like matrix metalloproteinases. Unlike endogenous mechanisms, exogenous (external) triggers including heat, light, ultrasound, and magnetic fields allow clinicians greater temporal and spatial control. The review compares structural platforms used to build these carriers, such as liposomes, polymeric micelles and nanoparticles, dendrimers, hydrogels, gold nanostructures, and quantum dots, assessing their load capacity, biocompatibility, and surface functionalization. We also discuss dual- and multi-stimuli-responsive designs that integrate more than one trigger within a single carrier for improved precision, and applications in oncology, inflammatory arthritis, gene therapy and neurological disorders. Finally, the review discusses key translational hurdles—anatomical and physiological challenges, toxicological profiling demands, manufacturing intricacies, and the lack of standardized evaluation methods—and proposes research priorities to accelerate clinical uptake of these technologies.