Photothermal-controlled NO-releasing Nanogels reverse epithelial-mesenchymal transition and restore immune surveillance against cancer metastasis.

Metastasis leads to high mortality among cancer patients. It is a complex, multi-step biological process that involves the dissemination of cancer cells from the primary tumor and their systemic spread throughout the body, primarily through the epithelial-mesenchymal transition (EMT) program and immune evasion mechanisms. It presents a challenge in how to comprehensively treat metastatic cancer cells throughout the entire stage of the metastatic cascade using a simple system. Here, we fabricate a nanogel (HNO-NG) by covalently crosslinking a macromolecular nitric oxide (NO) donor with a photothermal IR780 iodide-containing hyaluronic acid derivative via a click reaction. This enables stable storage and tumor-targeted, photothermia-triggered release of NO to combat tumor metastasis throughout all stages. Upon laser irradiation (HNO-NG+L), the surge in NO production within tumor cells impairs the NF-κB/Snail/RKIP signaling loop that promotes the EMT program through S-nitrosylation, thus inhibiting cell dissemination from the primary tumor. On the other hand, it induces immunogenic cell death (ICD) and thereby augments anti-tumor immunity, which is crucial for killing both the primary tumor and systemically distributed tumor cells. Therefore, HNO-NG+L, by fully leveraging EMT reversal, ICD induction, and the lethal effect of NO, achieved impressive eradication of the primary tumor and significant prevention of lung metastasis in a mouse model of orthotropic 4T1 breast tumor that spontaneously metastasizes to the lungs, extending the NO-based therapeutic approach against tumor metastasis.