pH‐Responsive STING‐Activating DNA Nanovaccines for Cancer Immunotherapy

Abstract

Cyclic dinucleotides (CDNs), such as c‐di‐GMP (CDG), are agonists for stimulator of interferon genes (STING) and are promising for cancer immunotherapy. Yet, the therapeutic efficacy of CDNs has been limited by poor delivery and biostability. Here, STING‐activating DNA nanovaccines (STING‐NVs) are developed, which biostabilize, deliver, and conditionally release CDG in the endosome of immune cells, elicit potent antitumor immune responses in murine and human immune cells, ameliorate immunosuppression in vitro and in the tumor microenvironment, and mediate potent cancer immunotherapy in a murine melanoma model. STING‐NVs have PLA‐b‐PEG in the core and cytosine (C)‐rich i‐motif DNA on the surface. i‐Motif DNA undergoes characteristic pH‐responsive conformational switch, allowing efficient CDG loading via C:G base pairing at physiological pH, and CDG release in sensitive response to acidic environment such as cell endosome. STING‐NVs protect CDG from enzymatic degradation. STING‐NVs facilitate cell delivery. Remarkably, STING‐NVs promote the endosome escape of CDG by ninefold, and potentiate antitumor immunity. STING‐NVs repolarize immunosuppressive M2‐like macrophages into antitumor M1‐like macrophages in vitro and in the tumor microenvironment of melanoma. In a poorly immunogenic murine melanoma model, intralesional STING‐NVs outperform liposomal CDG and fluoride‐CDG for melanoma immunotherapy. These results suggest the great potential of STING‐NVs for cancer immunotherapy.

Tumor‐Microenvironment‐Responsive Nanomedicine for Enhanced Cancer Immunotherapy

“…GSH is one of the most abundant reductive cellular metabolites, and it plays an important role maintaining the balance of the DEX-HAase nanoparticles 3-(bromomethyl)-4-methyl-2,5-furandione [24] PCL-Hyd-PEG vesicles Antigens HCP, adjuvants CpG ODN PCL-Hyd-PEG [25] Dendrigraft poly-l-lysines Zoledronic acid (ZA) 1,6-Bis(4-formylbenzoyloxy) hexane [26] RPTDH NPs R848 Poly-l-histidine (PHis) [27] Poly(ethylene glycol)-block-poly(diisopropanol amino ethyl methacrylate-co-hydroxyethyl methacrylate) (PDPA)-PPa Small interfering RNA (siRNA) OEI-C14 [28] PCPP hybrid micelles PD-L1-blockade siRNA, MTPP(PS) Amide bond [29] Nanogels PTX, IL-2 Chitosan polymers [30] CaCO 3 matrix CpG ODNs, IDOi, Ca 2+ CaCO 3 [31] H-MnO 2 nanoshells Ce6, DOX H-MnO 2 [32] Poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) NPs CDNs cytosine (C) [33] pHLIP [34] Hollow silica nanoparticle Catalase, Ce6 [35] PDPM NPs OVA PDPA tertiary amino groups [36] PD-L1 binding peptide conjugate (DCS) NPs DOX, D-PPA Maleic acid amide bond [37] Sensitive cluster nanoparticles (SCNs) 1. 4-[2((1R,2R)-2-Hydroxycyclohexylamino)benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide (BLZ-945), Pt-based prodrug Hydrophobic-hydrophilic transition [38] STING-NPs Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP)…”

“…More importantly, STING-NVs can revert M2-like macrophages into antitumor M1-like macrophages, which effectively improved the effect of immunotherapy. [33] In addition, Ji et al reported an antibody or Fc fragment modified with polypeptides to target solid tumors (Figure 3f). Fc fragments or therapeutic monoclonal antibodies were conjugated with low pH-responsive polypeptides.…”

“…Reproduced with permission. [ 33 ] Copyright 2020, Wiley‐VCH. f) The design of pH low insertion peptide (pHLIP)‐modified Fc molecules or antibodies and the proposed immunotherapeutic mechanism.…”

“…e) The signal ratio of FluoCDG outside/inside (O/I) endolysosome. Reproduced with permission [33]. Copyright 2020, Wiley-VCH.…”

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

“…[2] Ligands alternative to CDNs and nanoparticles or hydrogels carrying CDNs are being actively pursued in order to overcome these limitations for the clinical applications. [7,8,[11][12][13][14][15][16][17][18][19] Despite these ongoing efforts, a facile therapeutic intervention that targets STING pathway is highly desired.…”