Injectable Matrix Metalloproteinase-Responsive Polypeptide Hydrogels as Drug Depots for Antitumor Chemo-Immunotherapy

<b>Background:</b> The potential of injectable hydrogels as drug depots lies in their ability to achieve local and sustained co-delivery of chemotherapeutic drugs and immunostimulants for combined tumor therapy. <b>Method:</b> In this study, we devised a localized chemo-immunotherapeutic strategy by co-loading the chemotherapeutic drug, oxaliplatin (OXA), and the immune-checkpoint blockade (ICB) antibody, anti-programmed cell death protein ligand 1 (anti-PD-L1), into a matrix metalloproteinase (MMP)-responsive injectable poly(L-glutamic acid) hydrogel (MMP-gel). <b>Results:</b> The in situ gelation of hydrogels enables local retention of OXA and model antibody IgG, as well as MMP-triggered sustained release. Meanwhile, the OXA-loaded MMP-gel caused the immunogenic cell death (ICD) of tumor cells. When administered intratumorally in mice carrying B16F10 melanoma, the MMP-gel co-loaded with OXA and anti-PD-L1 (OXA&anti-PD-L1@MMP-gel) demonstrated superior tumor suppression efficacy and prolonged the survival time of the animals with low systemic toxicity. Meanwhile, the OXA&anti-PD-L1@MMP-gel induced an increase in CD8⁺ T cells and M1 macrophages within tumors, and a decrease in Treg cells and M2 macrophages, demonstrating that the drug-loaded system enhanced the antitumor immune response. Moreover, the OXA&anti-PD-L1@MMP-gel effectively inhibited the growth of distal tumors in a bilateral-tumor experiment. <b>Conclusions:</b> Consequently, the responsive hydrogel-based chemo-immunotherapy holds potential in tumor treatment.