Manganese-Based Nanoactivator Optimizes Cancer Immunotherapy via Enhancing Innate Immunity

Abstract

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are essential components of the innate immune sensors to cytosolic DNA and elicit type I interferon (IFN). Recent studies have revealed that manganese (Mn) can enhance cGAS and STING activation to viral infection. However, the role of Mn in antitumor immunity has not been explored. Here, we designed a nanoactivator, which can induce the presence of DNA in cytoplasm and simultaneously elevate Mn 2+ accumulation within tumor cells. In detail, amorphous porous manganese phosphate (APMP) NPs that are highly responsive to tumor microenvironment were employed to construct doxorubicin (DOX)-loaded and phospholipid (PL)-coated hybrid nanoparticles (PL/APMP-DOX NPs). PL/APMP-DOX NPs were stably maintained during systemic circulation, but triggered to release DOX for inducing DNA damage and Mn 2+ to augment cGAS/STING activity. We found that PL/APMP-DOX NPs with superior tumor-targeting capacity boosted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. Furthermore, the NPs increased production of type I IFN and secretion of pro-inflammatory cytokines (for example, TNF-α and IL-6). Consequently, PL/APMP-DOX NPs exhibited excellent antitumor efficacy and prolonged the lifespan of the tumor-bearing mice. Collectively, we developed a PL-decorated Mn-based hybrid nanoactivator to intensify immune activation and that might provide therapeutic potential for caner immunotherapy.

Cytosolic Delivery of Thiolated Mn‐cGAMP Nanovaccine to Enhance the Antitumor Immune Responses

“…The fixation cGAMP with Mn 2+ ion not only improved the stability of Mn‐cGAMP NVs, but also potentiated the activation of STING. [ 8 ] After intratumoral injection (i.t.) of Mn‐cGAMP NVs, Mn 2+ ion and cGAMP could be directly delivered into the cytoplasm of monocyte and induced lymph homing.…”

Biomimetic nanotherapy: core–shell structured nanocomplexes based on the neutrophil membrane for targeted therapy of lymphoma

“…However, it can quickly release DOX and SM in the weakly acidic environment of the tumor once it reaches the tumor tissue, exerting anti-tumor and anti-inflammatory activities. The nanodrug can realize the controllable release of DOX and SM with the help of the pH gradient between the systemic circulation and the tumor microenvironment [ 73 ]. The relationship between inflammation and tumor is mutual.…”

Harnessing Innate Immunity Using Biomaterials for Cancer Immunotherapy

“…Reproduced with permission. [ 79 ] Copyright 2020, American Chemical Society. D) PD‐L1‐leuckocyte‐labeled iron oxide NP with TGF‐ b induces ferroptosis‐mediated ICD, thus modulating tumor microenvironments with tumor‐suppressive mode.…”