NIR-elicited hydrogel contraction modulates rheological dynamics for spatiotemporally controlled metallo-drug release to potentiate cuproptosis-driven immunotherapy

Light-responsive control of hydrogel rheology enables precise spatiotemporal drug release. Light-triggered regulation of hydrogel rheology enables spatiotemporally controlled drug release. • Selective copper ion accumulation in tumors induces cuproptosis and synergizes with doxorubicin to promote immunogenic cell death, activating antitumor immunity. • Enhanced dendritic cell maturation and cytotoxic T-cell infiltration effectively convert "cold" tumors into "hot" ones, demonstrating potent antitumor efficacy in mouse models. Activation of cuproptosis has emerged as a paradigm-shifting therapeutic concept to improve cancer immunotherapy efficacy. Nevertheless, its clinical translation is impeded by the inability of existing delivery systems to achieve spatiotemporally precise copper surges within tumor tissues while minimizing systemic metal toxicity. To address this critical issue, we develop a metallo-drug system (HD-HMCS) featuring NIR-triggered and contractility-mediated co-delivery of copper ions and DOX for precisely tumor-localized induction of cuproptosis-immunotherapy. Upon NIR irradiation, the strong photothermal conversion of hollow mesoporous copper sulfide (HMCS) rapidly raises the local temperature to 40 °C, inducing contraction of the PNIPAAm-CS hydrogel shell. The resulting mechanical squeezing force destabilizes the HMCS framework, leading to an instantaneous burst release of the copper-DOX payload. This process induces the downregulation of FDX1 and promotes DLAT oligomerization, thereby enhancing copper-dependent cell death. Furthermore, this approach not only eradicates tumor cells through synergistic cuproptosis and immunogenic cell death (ICD) but also robustly activates systemic antitumor immunity by promoting DC maturation and CD8 + T cell infiltration. Collectively, this work establishes a novel and programmable paradigm for amplifying cuproptosis-immunotherapy, offering a transformative alternative to conventional metal-based nanotherapeutics and a promising synergistic strategy for precision cancer treatment. Download: Download high-res image (77KB) Download: Download full-size image