Activated Natural Killer Cells-Dependent Dendritic Cells Recruitment and Maturation by Responsive Nanogels for Targeting Pancreatic Cancer Immunotherapy.

Although enormous success has been obtained for dendritic cells (DCs)-mediated antigen-specific T cells anticancer immunotherapy in the clinic, it still faces major challenging problems: insufficient DCs in tumor tissue and low response rate for tumor cells lacking antigen expression, especially in low immunogenic tumors such as pancreatic cancer. Here, these challenges are tackled through tumor microenvironment responsive nanogels with prominent tumor-targeting capability by Panc02 cell membranes coating and inhibition of tumor-derived prostaglandin E2 (PGE2), aimed at improving natural killer (NK) cells activation and inducing activated NK cells-dependent DCs recruitment. The engineered nanogels can on-demand release acetaminophen to inhibit PGE2 secretion, thus promoting the activity of NK cells for non-antigen-specific tumor elimination. Furthermore, activated NK cells can secrete chemokines as CC motif chemokine ligand 5 and X-C motif chemokine ligand 1 to recruit immature DCs, and then promote DCs maturation and induce antigen-dependent CD8+ T cells proliferation for enhancing antigen-specific immunotherapy. Notably, these responsive nanogels show excellent therapeutic effect on Panc02 pancreatic tumor growth and postsurgical recurrence, especially combination of the programmed cell death-ligand 1 checkpoint-blockade immunotherapy. Therefore, this study provides a simple strategy for enhancing low immunogenic tumors immunotherapy through an antigen-independent way and antigen-dependent way synergetically.

Cancer cell membrane-coated nanogels as a redox/pH dual-responsive drug carrier for tumor-targeted therapy.

Nanocarriers have shown great advantages in increasing the efficiency of drug delivery and reducing drug side effects. However, their lack of targeting and on-demand drug release abilities will seriously limit their clinical application. Herein, we report tumor cell membrane coated nanogels (NGs) with redox/pH dual-responsive behavior for enhanced tumor chemotherapy. The cell membrane coating improves the tumor targeting efficiency, and stimuli-responsive drug release enhances the therapeutic effects. These NGs are well dispersed in PBS with an average size of 109.1 ± 5.2 nm and a narrow polydispersity index of 0.12. Both in vitro and in vivo studies indicate that these NGs can responsively release the therapeutic drug DOX under acidic conditions or high GSH concentrations and effectively inhibit tumor growth. Based on the results, this nanogel shows promise as a platform for tumor-targeted chemotherapy for future clinical translation.