Self-assembled melphalan hydrogel with nitric oxide delivery for synergistic chemoimmunotherapy.

Chemotherapy, a cornerstone in cancer treatment, faces significant challenges including inadequate drug targeting and tumor microenvironment limitations. Herein, we developed a small molecule self-assembled hydrogel loaded with nitric oxide (NO) donors S-nitrosoglutathione (GSNO) and chemotherapy drug Melphalan (Mel), termed GSNO-Mel hydrogel (GM Gel) by leveraging the unique property of Mel, self-assembled into hydrogels under ultrasonic conditions. Importantly, the sustained co-released of NO and Mel demonstrated synergistic therapeutic effects, not only inducing apoptosis and cell cycle arrest but also triggering a more potent immunogenic cell death (ICD), which may be attributed to NO's potential to reverse Mel-induced multidrug resistance in tumor cells, thereby significantly improving tumor-killing efficacy. The subsequent release of damage-associated molecular patterns (DAMPs) further amplified the immune response by activating dendritic cells. Additionally, NO played a critical role in remodeling the tumor microenvironment by polarizing tumor-associated macrophage toward M1 phenotype and alleviating hypoxia. Notably, the GM Gel system significantly suppressed tumor growth while eliciting anti-tumor immunity, highlighting its potential as a multifaceted therapeutic strategy for cancer treatment. Consequently, this work develops a facile strategy for engineering NO donor-integrated self-assembling hydrogels based on chemotherapeutic drugs, offering a promising approach to achieve chemoimmunotherapy through multiple mechanisms.