A spatiotemporally regulated drug delivery system with stage-specific thermosensitive gelation and photothermally triggered release for localized tumor therapy

To address the rapid systemic clearance and limited targeting efficiency of particulate drug delivery systems, localized drug delivery systems combining injectable hydrogels and nanoparticles have emerged as a promising alternative. This study introduces a photo-responsive multi-scale composite hydrogel platform for localized delivery of chemotherapeutic agents. In this study, doxorubicin-loaded photothermal nanoparticles (DOX@polydopamine@P(NIPAAm-<i>co</i>-AM), abbreviated as DPN) are prepared <i>via</i> a free radical polymerization route. Subsequently, they are incorporated into a thermosensitive PLGA-PEG-PLGA matrix to obtain the composite hydrogel (termed DPNP). The injectable DPNP hydrogel rapidly undergoes gelation as the temperature rises to the physiological level and forms an <i>in situ</i> depot at the targeted tissue due to the thermoresponsive sol-gel transition of the PLGA-PEG-PLGA matrix. Upon exposure to near-infrared light, polydopamine generates heat that induces a volume-phase transition of the DPN nanogels, thereby producing a precisely light-triggered release profile. The drug release rate can reach 87%. In the absence of light, the system maintains a sustained basal release rate. Overall, we have successfully developed a localized and spatiotemporally regulated drug delivery system capable of rapid NIR-triggered release coupled with sustained long-term release. The tumor suppression rate was 98.77%, providing a promising platform for precision-controlled cancer therapy.