Medicinal plant-derived mtDNA via nanovesicles induces the cGAS-STING pathway to remold tumor-associated macrophages for tumor regression.

Plant-derived nanovesicles (PDNVs) have been proposed as a major mechanism for the inter-kingdom interaction and communication, but the effector components enclosed in the vesicles and the mechanisms involved are largely unknown. The plant Artemisia annua is known as an anti-malaria agent that also exhibits a wide range of biological activities including the immunoregulatory and anti-tumor properties with the mechanisms to be further addressed. Here, we isolated and purified the exosome-like particles from A. annua, which were characterized by nano-scaled and membrane-bound shape and hence termed artemisia-derived nanovesicles (ADNVs). Remarkably, the vesicles demonstrated to inhibit tumor growth and boost anti-tumor immunity in a mouse model of lung cancer, primarily through remolding the tumor microenvironment and reprogramming tumor-associated macrophages (TAMs). We identified plant-derived mitochondrial DNA (mtDNA), upon internalized into TAMs via the vesicles, as a major effector molecule to induce the cGAS-STING pathway driving the shift of pro-tumor macrophages to anti-tumor phenotype. Furthermore, our data showed that administration of ADNVs greatly improved the efficacy of PD-L1 inhibitor, a prototypic immune checkpoint inhibitor, in tumor-bearing mice. Together, the present study, for the first time, to our knowledge, unravels an inter-kingdom interaction wherein the medical plant-derived mtDNA, via the nanovesicles, induces the immunostimulatory signaling in mammalian immune cells for resetting anti-tumor immunity and promoting tumor eradication.

Manganese nanodepot augments host immune response against coronavirus.

Interferon (IFN) responses are central to host defense against coronavirus and other virus infections. Manganese (Mn) is capable of inducing IFN production, but its applications are limited by nonspecific distributions and neurotoxicity. Here, we exploit chemical engineering strategy to fabricate a nanodepot of manganese (nanoMn) based on Mn2+. Compared with free Mn2+, nanoMn enhances cellular uptake and persistent release of Mn2+ in a pH-sensitive manner, thus strengthening IFN response and eliciting broad-spectrum antiviral effects in vitro and in vivo. Preferentially phagocytosed by macrophages, nanoMn promotes M1 macrophage polarization and recruits monocytes into inflammatory foci, eventually augmenting antiviral immunity and ameliorating coronavirus-induced tissue damage. Besides, nanoMn can also potentiate the development of virus-specific memory T cells and host adaptive immunity through facilitating antigen presentation, suggesting its potential as a vaccine adjuvant. Pharmacokinetic and safety evaluations uncover that nanoMn treatment hardly induces neuroinflammation through limiting neuronal accumulation of manganese. Therefore, nanoMn offers a simple, safe, and robust nanoparticle-based strategy against coronavirus. Electronic Supplementary Material: Supplementary material (RNA-seq data analysis, IFN and ISGs examination, in vitro viral infection, flow cytometry, ICP-MS, DHE staining, and detection of inflammatory factors) is available in the online version of this article at 10.1007/s12274-020-3243-5.

E. fischeriana Root Compound Dpo Activates Antiviral Innate Immunity.

E. fischeriana has long been used as a traditional Chinese medicine. Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrated that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA-seq analysis revealed that the induction of ISGs by viral infection could be synergized by Dpo. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7, or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection.