A matrix metalloproteinase-responsive hydrogel delivers dendritic cell-targeting nanoparticles for sustained antitumor immunity.

Despite its advances, the clinical efficacy of cancer immunotherapy remains limited due to inefficient immune response rate, high systemic toxicity, and the immunosuppressive nature of the tumor microenvironment (TME). Due to their three-dimensional mesh structure, hydrogels provide an effective platform for the local delivery of therapeutic drugs. Herein, we report a matrix metalloproteinase (MMP)-responsive poly(L-glutamic acid) hydrogel co-loaded with oxaliplatin (OXA) and DC-targeting resiquimod (R848)-encapsulated nanoparticles (R@pep-PNP) to address these challenges. The hydrogel had TME-specific degradation and sustained drug release capacity due to its MMP-cross-linked network. OXA released from the hydrogel could induce immunogenic cell death (ICD) in tumor cells and the generation of tumor antigens, while R848 released from the DC-targeting nanoparticles promoted DCs maturation and lymph node draining. In mouse melanoma models, the hydrogel co-loaded with OXA and R@pep-PNP elicited a robust systemic anti-tumor immune response, effectively inhibited tumor growth and recurrence, and established a durable immune memory. Additionally, the treatment with the drug-loaded hydrogel resulted in minimal systemic side effects. Overall, this study presents an efficient hydrogel platform for overcoming immunosuppressive barriers and enhancing anti-tumor immunity.