In-situ injectable hydrogel for near-infrared-regulated hyperthermic perfusion therapy of triple-negative breast cancer.

Hyperthermic perfusion therapy (HPT) is an emerging and effective treatment for intracavitary tumors, involving circulating a heated solution directly into body cavities such as the peritoneal or pleural spaces, targeting tumors more effectively while minimizing systemic toxicity. However, the clinical application of HPT is currently restricted to intracavitary tumors, and its efficacy is hampered by the up-regulation of thermal stress resistance genes, which enhance the thermal tolerance of cancer cells. Herein, we developed a temperature-sensitive methyl cellulose hydrogel with injectability and removability to enable targeted HPT for the triple-negative breast cancer (TNBC). Using bioinformatics screening, we identified 17-allylamino-17-demethoxygeldanamycin as a potent inhibitor and incorporated it alongside biocompatible cuttlefish ink-derived nanoparticles (CINPs), a natural photothermal agent, into the temperature-sensitive hydrogel. Under near-infrared (NIR) irradiation, CINPs mediate photothermal tumor ablation, while 17-allylamino-17-demethoxygeldanamycin reduces tumor cell resistance to hyperthermia. Moreover, the temperature-responsive phase transition of the hydrogel allows for its complete removal post-treatment, extending the scope of HPT beyond intracavitary tumors and minimizing inflammation at the injection site. This material-engineered HPT approach, achieved remarkable outcomes in both orthotopic and metastatic tumor models, inhibiting breast cancer progression and lung metastasis. These findings highlight the potential of materials-based HPT as an effective treatment for TNBC.