Intravenous administration of IL-12 encoding self-replicating RNA-lipid nanoparticle complex leads to safe and effective antitumor responses.

Interleukin 12 (IL-12) is a potent immunostimulatory cytokine mainly produced by antigen-presenting cells (e.g., dendritic cells, macrophages) and plays an important role in innate and adaptive immunity against cancers. Therapies that can synergistically modulate innate immunity and stimulate adaptive anti-tumor responses are of great interest for cancer immunotherapy. Here we investigated the lipid nanoparticle-encapsulated self-replicating RNA (srRNA) encoding IL-12 (referred to as JCXH-211) for the treatment of cancers. Both local (intratumoral) and systemic (intravenous) administration of JCXH-211 in tumor-bearing mice induced a high-level expression of IL-12 in tumor tissues, leading to modulation of tumor microenvironment and systemic activation of antitumor immunity. Particularly, JCXH-211 can inhibit the tumor-infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). When combined with anti-PD1 antibody, it was able to enhance the recruitment of T cells and NK cells into tumors. In multiple mouse solid tumor models, intravenous injection of JCXH-211 not only eradicated large preestablished tumors, but also induced protective immune memory that prevented the growth of rechallenged tumors. Finally, intravenous injection of JCXH-211 did not cause noticeable systemic toxicity in tumor-bearing mice and non-human primates. Thus, our study demonstrated the feasibility of intravenous administration of JCXH-211 for the treatment of advanced cancers.

Growth of grasses and forbs, nutrient concentration, and microbial activity in soil treated with microbeads.

Microplastics have emerged as an important threat to terrestrial ecosystems. To date, little research has been conducted on investigating the effects of microplastics on ecosystem functions and multifunctionality. In this study, we conducted the pot experiments containing five plant communities consisting of Phragmites australis, Cynanchum chinense, Setaria viridis, Glycine soja, Artemisia capillaris, Suaeda glauca, and Limonium sinense and added polyethylene (PE) and polystyrene (PS) microbeads to the soil (contained a mixture of 1.5 kg loam and 3 kg sand) at two concentrations of 0.15 g/kg (lower concentration, hereinafter referred to as PE-L and PS-L) and 0.5 g/kg (higher concentration, hereinafter referred to as PE-H and PS-H) to explore the effects of microplastics on total plant biomass, microbial activity, nutrient supply, and multifunctionality. The results showed that PS-L significantly decreased the total plant biomass (p = 0.034), primarily by inhibiting the growth of the roots. ß-glucosaminidase decreased with PS-L, PS-H, and PE-L (p < 0.001) while the phosphatase was noticeably augmented (p < 0.001). The observation suggests that the microplastics diminished the nitrogen requirements and increased the phosphorus requirements of the microbes. The decrease in ß-glucosaminidase diminished ammonium content (p < 0.001). Moreover, PS-L, PS-H, and PE-H reduced the soil total nitrogen content (p < 0.001), and only PS-H considerably reduced the soil total phosphorus content (p < 0.001), affecting the ratio of N/P markedly (p = 0.024). Of interest, the impacts of microplastics on total plant biomass, ß-glucosaminidase, phosphatase, and ammonium content did not become larger at the higher concentration, and it is observable that microplastics conspicuously depressed the ecosystem multifunctionality, as microplastics depreciated single functions such as total plant biomass, ß-glucosaminidase, and nutrient supply. In perspective, measures to counteract this new pollutant and eliminate its impact on ecosystem functions and multifunctionality are necessary.