A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Abstract

Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn 2+ ions have been recently discovered to directly activate the cyclic GMP-AMP (cGAMP) synthase (cGAS) and augment cGAMP-STING binding affinity. Here, a PEGylated manganese(II) phosphate (MnP-PEG) nanocluster is developed with high biocompatibility and potent capacity to stimulate the cGAS-STING pathway. MnP-PEG nanoclusters activate the immature bone marrow-derived dendritic cells (DCs) leading to 57.3-and 13.3-fold higher production of interferon and interleukin-6 than free cGAMP, respectively. The potent STING activation capacity is likely due to the efficient cellular internalization of MnP-PEG nanoclusters by DCs and acid-triggered release of Mn 2+ ions in the endolysosomes. Intratumoral administration of MnP-PEG nanoclusters markedly enhances tumor infiltration as well as maturation of DCs and macrophages, and promotes activation and cytotoxicity of T cells and natural killer cells in the tumor. MnP-PEG nanocluster in combination with a checkpoint inhibitor leads to significant tumor regression in the B16F10 murine melanoma model without any overt toxicities.

Combination of Metal‐Phenolic Network‐Based Immunoactive Nanoparticles and Bipolar Irreversible Electroporation for Effective Cancer Immunotherapy

“…[ 10 ] As a result, delivery of Mn ions to APCs using nanoparticles can increase the efficiency of APC priming while minimizing side effects. [ 11 ]…”

“…[10] As a result, delivery of Mn ions to APCs using nanoparticles can increase the efficiency of APC priming while minimizing side effects. [11] Nucleic acid-based immunoadjuvants can effectively induce M1 polarization of macrophages. [12] CpG-oligodeoxynucleotide (CpG-ODN), an agonist of toll-like receptor 9 (TLR9), is the most actively studied nucleic acid-based immunoadjuvant.…”

A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy

“…Compared with free Mn 2+ ions, nanoparticle modification can increase the retention time of Mn 2+ in the tumor and improve biosafety in vivo [7]. Importantly, sustained release of Mn 2+ from enable the maximization activation of STING pathway, thus leading to potent tumor killing ability [8][9][10]. Hence, it is of great significance to construct a nanoprobe with acidic response and sustained release behavior for fully exploiting the MR imaging and STING activation functions of Mn 2+ .…”

Physical and Chemical Cues at the Nano–Bio Interface for Immunomodulation

“…[49] In recent years, a number of manganese-based nanomaterials have been developed based on the activation of cGAS/STING pathway, [50] which can catalyze the synthesis of cyclic GMP-AMP and improve the binding affinity of cGAMP-STING. [51] For instance, Gao et al [52] designed a PEGylated manganese phosphate nanocluster (MnP-PEG) STING agonist. Released Mn 2 + can activate STING signaling effectively, thus promoting the maturation of CD8 + T cells.…”