NIR‐Induced Photoswitching Hybrid DNA Nanoconstruct‐Based Drug Delivery System for Spatiotemporal Control of Stem Cell Fate

Abstract Precise spatiotemporal control of drug delivery is extremely valuable for regulating stem cell fate, particularly in stem cell differentiation. A novel near‐infrared (NIR)‐mediated spatiotemporal delivery system is reported combining photo‐switchable arylazopyrazole (AAP)‐containing DNA strands and upconversion nanoparticles (UCNPs). This nano‐drug delivery system (NDDS) enables precise modulation of DNA duplex structures in response to NIR stimuli, overcoming the limitations of traditional UV‐responsive systems. AAP derivatives with enhanced photoswitching efficiency (≈98%) and significantly improved cis‐form stability are engineered. The successful delivery of curcumin, a neurogenic compound with an affinity for the minor groove of DNA, to human neural stem cells (NSCs) is achieved using UCNP‐DNA‐AAP constructs. Upon 980 nm NIR light exposure, UCNPs efficiently up‐converted NIR to UV light, triggering AAP photoisomerization and DNA dissociation, thus releasing curcumin. This approach enabled efficient spatiotemporal control over NSC differentiation while facilitating neuroprotection. Immunofluorescence and gene expression analyses demonstrated enhanced neuronal mRNA levels and neurite outgrowth in treated cells. In short, the NIR‐mediated photo‐switchable NDDS offers a precise and innovative approach to control stem cell fate, enabling spatiotemporal regulation of cellular processes. This technology has significant potential applications in nanomedicine and neuroscience, where precise drug delivery is crucial for targeted neural interventions.