Near-infrared responsive theranostic platforms: toxicological challenges, biological interactions, and clinical translation

The disease microenvironment is a complex milieu containing unique biochemical and biophysical cues, such as acidosis, oxidative stress, hypoxia, enzymatic imbalance, and microorganisms, which influence not only the effectiveness of treatments but also the fate and safety of the nanomedicine. NIR-responsive dyes and dye-conjugated nanomaterials have attracted considerable attention for diagnostic and therapeutic applications owing to their deep tissue penetration, external-stimulus activation, and precise spatiotemporal control. Despite notable progress in developing NIR-responsive systems for cancer, inflammatory diseases, and infections, their clinical use is limited by issues such as toxicity, degradation, biodistribution, accumulation, persistence, and immune reactions to nanomaterials. Importantly, recent studies have shown that the disease microenvironment can significantly affect the degradation, activation, bioactivity, and toxicity of NIR-responsive systems, yet these issues remain scattered in the literature. Specific attention is paid to structure–toxicity relationships, phototoxicity, immunotoxicity, biodegradability, biodistribution, organ-specific accumulation, and long-term safety, as well as emerging contrasts between NIR-I and NIR-II-based systems. We additionally elaborate on advanced experimental models, regulatory approaches, and safety and design approaches, such as biodegradable systems, renal-clearance-based systems, and smart activated nanomaterials.